Thiazole derivatives, processes for production thereof and pharmaceutical compositions comprising the same

ABSTRACT

Compounds of the formula: ##STR1## wherein A is S, SO, or SO2, R1 is H or acyl, R2 is H, alkyl, hydroxyalkyl, halogen or carboxy, and R3 is pyridyl are claimed. The compounds are useful as therapeutic agents for the treatment of e.g. rheumatism, nephritis and thrombocytopenia.

The application is a continuation of application Ser. No. 07/554,413,filed on Jul. 19, 1990, now abandoned.

This invention relates to new thiazole derivatives.

More particularly, this invention relates to new thiazole derivativesand pharmaceutically acceptable salts thereof which have pharmacologicalactivities, processes for production thereof, pharmaceuticalcompositions comprising the same and methods of use thereof.

Accordingly, one object of this invention is to provide new and usefulthiazole derivatives and pharmaceutically acceptable salt thereof.

Another object of this invention is to provide processes for productionof said thiazole derivatives and pharmaceutically acceptable saltsthereof.

A further object of this invention is to provide pharmaceuticalcompositions comprising said thiazole derivatives of pharmaceuticallyacceptable salts thereof.

A still further object of this invention is to provide methods of usingsaid thiazole derivatives or pharmaceutically acceptable salts thereoffor therapeutic treatment of rheumatism, nephritis, thrombocytopenia,tumor or side effect of an antitumor agent in human being and animals.

The object thiazole derivatives of this invention are novel andrepresented by the following general formula (I): ##STR2## wherein R¹ ishydrogen or acyl which may be substituted with halogen,

R² is hydrogen, lower alkyl, hydroxy(lower)alkyl, halogen or carboxy,

A is --CH₂ --, --CO--, --C(═NOR⁴)-- [wherein R⁴ is lower alkyl],##STR3## [wherein m is 0, 1 or 2], and R³ is aryl which may besubstituted with halogen, hydroxy, lower alkoxy, nitro, amino oracylamino; or N-containing unsaturated heterocyclic group which may besubstituted with lower alkyl, amino, hydroxy or halo(lower)alkyl.

The object compound (I) of the present invention can be prepared by thefollowing processes. ##STR4## wherein R¹, R², R³, R⁴ and A are each asdefined above,

R⁵ is acyl which may be substituted with halogen,

R⁶ is acylamino,

X is halogen,

l is 0 or 1,

n is 0 or 1 and

q is 1 or 2,

provided that q is 2 when n is 1.

A kind of the starting compounds [II] can be prepared by the process asillustrated in the following. ##STR5## wherein R¹ and x are each asdefined above, and

R⁷ is lower alkyl or hydroxy(lower)alkyl.

In the above and subsequent description of the present specification,suitable examples and illustrations for the various definitions to beincluded within the scope of the invention are explained in detail asfollows:

The term "lower" is intended to mean 1 to 6 carbon atom(s), unlessotherwise indicated.

Suitable "lower alkyl" may be a straight or branched one such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl orthe like.

Suitable example of "lower alkyl" moiety in the term"hydroxy(lower)alkyl" and "halo(lower)alkyl" can be referred to the onesas exemplified above.

Suitable "halo(lower)alkyl" may include "monohalo(lower)alkyl", [e.g.chloromethyl, bromomethyl fluoromethyl, etc.], "dihalo(lower)alkyl"[e.g. dichloromethyl, dibromomethyl, difluoromethyl, etc.] and"trihalo(lower)alkyl" [e.g. trichloromethyl, tribromomethyl,trifluoromethyl, trifluoroethyl, etc.] and the like.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy and thelike.

Suitable "halogen" may include fluorine, chlorine, bromine and iodine.

Suitable examples of "aryl" may include phenyl, tolyl, xylyl, cumenyl,naphthyl, and the like.

Suitable acyl may include an aliphatic acyl, an aromatic acyl and analiphatic acyl substituted with aromatic group(s).

The aliphatic acyl may include saturated or unsaturated, acyclic orcyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.),lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), loweralkanesulfonyl [e.g. methanesulfonyl, ethanesulfonyl, propanesulfonyl,butanesulfonyl, pentanesulfonyl, hexanesulfonyl, etc.], lower alkenoyl(e.g. acryloyl, methacryloyl, crotonoyl, etc.), carbamoyl and the like.

The aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl,etc.) and the like.

The aliphatic acyl substituted with aromatic group(s) may includear(lower)alkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl,phenylpropionyl, phenylhexanoyl, etc.), ar(lower)alkoxycarbonyl such asphenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl,phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. phenoxyacetyl,phenoxypropionyl, etc.), and the like.

Suitable example of "acyl" moiety in the term of "acylamino" can bereferred to the ones as exemplified above.

Suitable "N-containing unsaturated heterocyclic group" may be onecontaining at least one nitrogen atom and may include monocyclic orpolycyclic heterocyclic group, and preferable heterocyclic group may beunsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl(e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl(e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.),etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl,etc.);

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), etc.; unsaturated condensed heterocyclicgroup containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like. Said"heterocyclic group" may have 1 to 4 substituents such as lower alkyl asexemplified above.

Suitable pharmaceutically acceptable salts of the object compounds [I]are conventional non-toxic salts and include an organic acid salt [e.g.formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate,benzenesulfonate, toluenesulfonate, etc.], an inorganic acid salt [e.g.hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with anamino acid [e.g. arginine, glutamic acid, ornithine, etc.], a metal saltsuch as an alkali metal salt [e.g. sodium salt, potassium salt, etc.]and an alkaline earth metal salt [e.g. calcium salt, magnesium salt,etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.], and the like.

In this respect, it is to be noted that the compounds [Ia] to [Ip] areincluded within the scope of the compound [I], and accordingly thesuitable salts of these compounds [Ia] to [Ip] are to be referred tothose as exemplified for the object compounds [I] in the above.

The processes for preparing the object compound [I] or salts thereof areexplained in detail in the following.

PROCESS 1

The object compound [Ib] or its salt can be prepared by deacylating acompound [Ia] or its salt.

Suitable method for this deacylation reaction may include conventionalone such as hydrolysis and the like.

Hydrolysis is preferably carried out in the presence of an acid.

Suitable acid may be an inorganic acid [e.g. hydrochloric acid,hydrobromic acid, sulfuric acid, etc.], an organic acid [e.g. formicacid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc.], an acidic ion-exchange resin andthe like. In case that the organic acid such as trifluoroacetic acid andp-toluenesulfonic acid is used in this reaction, the reaction ispreferably carried out in the presence of cation trapping agents [e.g.anisole, etc.].

The acid suitable for this hydrolysis can be selected according to thekinds of the acyl group to be removed.

The hydrolysis is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, tert-butyl alcohol, tetrahydrofuran,N,N-dimethylformamide, dioxane or a mixture thereof, and further theabove-mentioned acids can also be used as a solvent when they are inliquid.

The reaction temperature of this hydrolysis is not critical, and thereaction is usually carried out under cooling, at ambient temperature orunder heating.

In this process, when the starting compound [Ia] or its salt has aacylamino group for R³, the group is also converted to an amino group.

PROCESS 2

The object compound [Ic] or its salt can be prepared by reacting acompound [II] or its salt with a compound [III] or its salt.

Suitable salts of the compound [II] and [III] may be the same as thoseexemplified as base salts of the object compound [I].

This reaction is usually carried out in a solvent such as methanol,ethanol, propanol, tetrahydrofuran, dioxane, dimethylformamide or anyother organic solvent which does not adversely influence the reaction.

In case that a free form of the compound [III] is used in this reaction,the reaction is preferably carried out in the presence of a conventionalbase, such as alkali metal hydride [e.g. sodium hydride, potassiumhydride, etc.], alkaline earth metal hydride [e.g. calcium hydride,magnesium hydride, etc.], alkali metal hydroxide [e.g. sodium hydroxide,potassium hydroxide, etc.], alkali metal carbonate [e.g. sodiumcarbonate, potassium carbonate, etc.], alkali metal bicarbonate [e.g.sodium bicarbonate, potassium bicarbonate, etc.], alkali metal fluoride[e.g. potassium fluoride, cesium fluoride, etc.], alkali metal alkoxide[e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.],trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,5-diazabicyclo[5,4,0]undecene-5 or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature or under cooling, warming or heating.

PROCESS 3

The object compound [Ie] or its salt can be prepared by reducing acompound [Id] or its salt.

The reduction can be carried out in a conventional manner, namely,chemical reduction or catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal (e.g. stannum, zinc, iron, etc.) and ammoniumchloride or an base (e.g. ammonia, sodium hydroxide, etc.), acombination of metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g. chromium chloride, stannous chloride, chromium acetate, etc.) andan organic or inorganic acid (e.g. formic acid, acetic acid, propionicacid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.), alkali metal borohydride (e.g. lithiumborohydride, sodium borohydride, potassium borohydride, etc.) alkalimetal cyanoborohydride (e.g. sodium cyanoborohydride, etc.) or alkalimetal ammonium hydride (e.g. lithium aluminum hydride, etc.) or thelike.

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalyst (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalyst (e.g. palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,etc.), nickel catalyst (e.g. reduced nickel, nickel oxide, Raney nickel,etc.), cobalt catalyst (e.g. reduced cobalt, Raney cobalt, etc.), ironcatalyst (e.g. reduced iron, Raney iron, etc.), copper catalyst (e.g.reduced copper, Raney copper, Ullman copper, etc.) or the like.

The reduction of this process is usually carried out in a solvent suchas water, alcohol (e.g. methanol, ethanol, propanol, etc.), acetic acid,dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, orany other organic solvent which does not adversely influence thereaction, or a mixture thereof. In case above-mentioned reducing agentis liquid, it can be also used as a solvent.

The reaction is preferably carried out under cooling to warming orheating.

PROCESS 4

A compound [Ig] or its salt can be prepared by subjecting a compound[If] or its salt to oxidation.

Oxidation in this process is carried out in a conventional manner with aconventional oxidizing agent which can oxidize a --S-- group into --SO--or --SO₂ -- group, or --SO-- group into --SO₂ -- group.

Suitable example of such oxidizing agent are inorganic peracid or itssalt (e.g. periodic acid, persulfuric acid, etc.) or the sodium orpotassium salt thereof, an organic peracid or its salt (e.g. perbenzoicacid, 3-chloroperbenzoic acid, performic acid, peracetic acid,chloroperacetic acid, trifluoroperacetic acid, etc. or the sodium orpotassium salt thereof, etc.), ozone, hydrogen peroxide, urea-hydrogenperoxide and the like.

The present reaction is preferably conducted in the presence of acompound comprising a Group Vb or VIb metal in the Periodic Table, forexample, tungstic acid, molybdic acid, vanadic acid, etc. or their saltwith an alkali metal (e.g. sodium, potassium, etc.), an alkaline earthmetal (e.g. calcium, magnesium, etc.) or ammonium, etc., or vanadiumpentoxide.

The present oxidation is usually conducted in a solvent such as water,acetic acid, ethyl acetate, chloroform, dichloromethane,tetrahydrofuran, dioxane, N,N-dimethylformamide or any other solventwhich does not give bad influence to the present reaction.

There is not particular limitation to the reaction temperature, and thepresent reaction is usually conducted at ambient temperature or undercooling.

PROCESS 5

The object compound [Ii] or its salt can be prepared by subjecting acompound [Ih] or its salt to oxidation.

Suitable oxidizing agent may include hypochlorite compound (e.g.tert-butyl hypochlorite, etc.), permanganate (e.g. potassiumpermanganate, etc.), or any other conventional oxidizing agent.

This reaction is usually carried out in a solvent such as water, aceticacid, diethyl ether, dioxane, dichloromethane, chloroform,N,N-dimethylformamide, dimethyl sulfoxide, or any other organic solventwhich does not adversely influence the reaction, or a mixture thereof.In case the above-mentioned acid is liquid, it can be also used as asolvent.

The reaction can be carried out under cooling to warming or heating.

PROCESS 6

The object compound [Ik] or its salt can be prepared by halogenating acompound [Ij] or its salt.

Suitable halogenating agent of this reaction may include conventionalones for example, halogen [e.g. chlorine, bromine, iodine, etc.],sulfuryl halide [e.g. sulfuryl chloride, sulfuryl bromide, etc.],N-halosuccinimide [e.g. N-chlorosuccinimide, N-bromosuccinimide, etc.],pyridinium hydrohalide perhalide [e.g. pyridinium hydrobromideperbromide, pyridinium hydrochloride perchloride, etc.], quarternaryammonium perhalide [e.g. phenyltrimethylammonium perbromide, etc.],ω-trihaloacetophenone [e.g. ω-tribromoacetophenone, etc.], cupric orpotassium bromide, selenium oxychloride, or the like. These halogenatingagents may be selected according to the kind of the starting compound[Ij] to be used.

This reaction is usually carried out in a conventional solvent such aschloroform, methylene chloride, carbon tetrachloride, acetic acid, amixture of hydrogen halide [e.g. hydrogen bromide, hydrogen chloride,etc.] and acetic acid, water, dimethylformamide or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling, at ambient temperature or under warming orheating.

PROCESS 7

The object compound [Ia] or its salt can be prepared by acylating acompound [Ib] or its reactive derivatives at the amino group or a saltthereof.

Suitable reactive derivatives at the amino group of the compound [Ib]include conventional ones used in amidation for example, Schiff's basetype imino or its tautomeric enamine type isomer formed by reaction of acompound [Ib] with a carbonyl compound, a silyl derivative formed byreaction of a compound [Ib] with a silyl compound such astrimethylsilylacetamide, bis(trimethylsilyl)acetamide or the like, aderivative formed by reaction of a compound [Ib] with phosphorustrichloride or phosgene, and the like.

Suitable acylating agent to be used in this reaction includes an organicacid such as alkanoic acid [e.g. formic acid, acetic acid, propionicacid, etc.], arenecarboxylic acid (e.g. benzoic acid, toluenecarboxylicacid, etc.) which may have halogen, lower alkanesulfonic acid [e.g.methanesulfonic acid, etc.], arylisocyanate [e.g. phenylisocyanate,etc.] which may have halogen and their reactive derivative.

The suitable reactive derivative may be a conventional one such as anacid halide [e.g. acid chloride, acid bromide, etc.], an acid azide, anacid anhydride, an activated amide, an activated ester and the like.When free acid is used as an acylating agent, the acylation reaction maypreferably be conducted in the presence of a conventional condensingagent such as N,N'-dicyclohexylcarbodiimide or the like.

This reaction is usually carried out in a solvent which does notadversely influence the reaction such as water, tetrahydrofuran,chloroform, dioxane, pyridine, methylene chloride, N,N-dimethylformamideor the like.

The reaction temperature is not critical and the reaction can be carriedout at any temperature under cooling to heating.

PROCESS 8

The object compound [Il] or its salt can be prepared by acylating acompound [Ie] or its reactive derivatives at the amino group or a saltthereof.

Suitable reactive derivatives at the amino group are to be referred tothose as exemplified in Process 7.

This reaction may be carried out in substantially the same manner asProcess 7, and therefore the reaction mode and reaction conditions [e.g.acylating agent, solvent, reaction temperature, etc.] of this reactionare to be referred to those as explained in Process 7.

PROCESS 9

The object compound [Im] or its salt can be prepared by reacting acompound [IV] or its salt with a compound [V] or its salt.

Suitable salts of the compounds [IV] and [V] may be the same as thoseexemplified for the compound [I].

Suitable examples of the compound [V] may be thiocarbamoyl derivativessuch as thiourea, N-acylthiourea [e.g. N-formylthiourea,N-acetylthiourea, N-propionylthiourea, N-benzoylthiourea which may besubstituted with halogen, etc.] or the like.

This reaction is usually carried out in a conventional solvent such aswater, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane,chloroform, methylene chloride, dimethylacetamide, dimethylformamide orany other organic solvent which does not adversely influence thereaction. Among these solvents, hydrophilic solvents may be used in amixture with water.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature or under warming or heating.

PROCESS 10

The object compound [In] or its salt can be prepared by reacting acompound [VI] or its salt with a compound [V] or its salt.

Suitable salts of the compound [VI] may be the same as those exemplifiedfor the object compound [I].

This reaction may be carried out in substantially the same manner asProcess 9, and therefore the reaction mode and reaction conditions [e.g.solvent, reaction temperature, etc.] of this reaction are to be referredto those as explained in Process 9.

PROCESS 11

The object compound [Ip] or its salt can be prepared by reacting acompound [Io] or its salt with a hydroxylamine derivative [VII] or itssalt.

A suitable salt of a hydroxylamine derivative [VII] may be a hydrohalide(e.g. hydrochloride, etc.).

This reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g. methanol, ethanol, propanol, etc.),tetrahydrofuran, dioxane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adverselyinfluence the reaction. In case the compound [VII] is liquid, it can bealso used as a solvent.

The reaction temperature is not critical, and the reaction can becarried out under cooling to warming or heating.

The process for preparing the starting compound [II] or its salt isexplained in detail in the following.

PROCESS A

The compound [II'] or its salt can be prepared by halogenating acompound [VIII] or its salt.

Suitable salts of the compounds [II'] and [VIII] may be the same asthose exemplified for the object compound [I].

This reaction may be carried out in substantially the same manner asProcess 6, and therefore the reaction mode and reaction conditions [e.g.halogenating agent, solvent, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 6.

The object compounds and pharmaceutically acceptable salts thereof arenovel and exhibit pharmacological activities and are useful for thetreatment and prophylaxis of rheumatism (e.g. rheumarthritis, etc.),nephritis, thrombocytopenia [e.g. idiopathic thrombocytopenic purpura,secondary thrombocytopenic purpura, thrombocytopenia due to a sideeffect of an antitumor agent (e.g. mitomycin C, etc.) etc.], tumor, sideeffect of an antitumor agent (e.g. decrease of body weight, etc.) andthe like.

In order to show the utility of the object compounds [I], antirheumatic,anti-nephritic and platelet number-increasing activities and alleviatingactivity for side effect of antitumor agent of the object compounds [I]are explained in the following.

ANTIRHEUMATIC ACTIVITY Test 1 Effect on collagen induced arthritis inmice Method

Ten male DBA/1 mice were used per group. Type II bovine collagen wasdissolved in 0.1M acetic acid and emulsified in complete Freund'sadjuvant (CFA). Mice were primed with 125 μg of Type II collagen in CFAintradermally at the base of the tail. Mice were challenged after 21 daywith the same procedure. From the day of challenge, drug wasadministered orally once a day for 3 weeks and mice were inspectedweekly for visual signs of arthritis. To evaluate the effect of drugs,an arthritic index was used. Arthritic index was obtained by scoringeach limb 0-3 severity, representing joint swelling and erythema (Grade1), visible joint disorder (Grade 2) and detectable joint ankylosis(Grade 3), and by summing up scores of four limbs.

    ______________________________________    Results:    Compounds       Dose level                              Inhibition    a compound of   (mg/kg)   (%)    ______________________________________    Example 18      100       50    Example 23      100       51    Example 27      100       46    Example 29      100       57    Example 30      100       35    Example 33      100       44    Example 37      100       50    Example 38      100       31    Example 40      100       44    ______________________________________

ANTI-NEPHRITIC ACTIVITY Test 2 Effect on chloric GVH disease (nephritis)Method

Six weeks old female (57BL/6×DBA/2)F₁ and DBA/2 mice were used.Graft-versus-host (GVH) disease was induced in (57BL/6×DBA/2)F₁ micewith two injections of DBA/2 spleen cells given 5 days apart. Eachinjection contained 5×10⁷ cells. From 3 days after second cellinjection, drug was administered orally once a day for 8 weeks. Toassess the renal disease, at 8 weeks after last cell injection,proteinuria were measured. The concentration of serum albumin in theurine was determined by the single radial immunodiffusion method usingrabbit anti-mouse serum albumin antiserum. Ten mice were used per group.Antinephritic activity of the compound was expressed the inhibition ofalbumin in urine.

    ______________________________________    Results:    Compounds    Dose level                           Inhibition of    a compound of                 (mg/kg)   albumin in urine (%)    ______________________________________    Example  7   100       52    Example 18   100       98    Example 23   100       96    Example 29   100       90    Example 30   100       98    Example 33   100       70    Example 35   100       74    Example 37   100       100    Example 38   100       78    ______________________________________

PLATELET NUMBER-INCREASING ACTIVITY Test 3 Increasing effect on theplatelet number decreased by mitomycin C Method

A test compound was given orally once a day for 5 days to male ddY miceaged 6 to 7 weeks. The animals were used in groups of 10. Mitomycin C(hereinafter referred to as MMC) at a dose of 3.2 mg/kg was givenintravenously to mice on day 0, 2, and 4 after the initial dosing withthe test compound. The number of platelets were counted 5 days after thefinal dosing with the test compound, in which mice were bled from theorbital plexus and the platelets were counted with an automatic bloodanalyzer. The number of platelets of each group was calculated on thebasis of the number of platelets (%) obtained from the non-test compoundgroup.

    ______________________________________    Results:    Compounds      Dose level                             Number of    a compound of  (mg/kg)   platelets (%)    ______________________________________    Example 14     32        164    Example 15     32        150    Example 30     32        184    Example 31     32        154    Example 33     32        210    Example 40     32        165    Example 68     32        135    ______________________________________

ALLEVIATING ACTIVITY FOR SIDE EFFECT OF ANTITUMOR AGENT Test 4 Restoringeffect on the body weight decreased by MMC Method

A test compound was given orally once a day for 5 days to male ddY miceaged 6 to 7 weeks. The animals were used in groups of 10. MMC at a doseof 3.2 mg/kg was given intravenously to mice on day 0, 2, and 4 afterthe initial dosing with the test compound. The body weight of mice weremeasured on day 0 and day 8.

The body weight of non-test compound group which was only administeredMMC as above was measured on day 0 and day 8 as a control.

    ______________________________________    Results:                Dose of                test compound                           Body weight (g)                (mg/kg)    day 0    day 8    ______________________________________    MMC & a compound                  100          32.7     31.1    of Example 30    MMC & a compound                  100          32.6     31.1    of Example 31    MMC & a compound                  100          32.6     30.2    of Example 68    MMC (no test  --           32.6     28.6    compound)                         (mean of 10 mice)    ______________________________________                          [I] and pharmaceutically acceptable salts thereof are     used in the form of conventional pharmaceutical composition such as     powders, fine granules, granules, tablets, dragee, microcapsules,     capsules, suppository, solution, suspension, emulsion, syrups and the     like. If desired, diluents or disintegrators (e.g. sucrose, lactose,     starch, crystalline cellulose, low-substituted hydroxypropyl cellulose,     synthetic aluminum silicate, etc.), binding agents (e.g. cellulose,     methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,     polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic,     polyethyleneglycol, etc.), coloring agents, sweeting agents, lubricant     (e.g. magnesium stearate, etc.) or the like, may be dispensed with said     composition.

The dosage of said composition according to this invention depends onthe patient's age, body weight, condition, etc., and it is generallyadministered by the oral route at the daily dose level of 1 mg to 1 g asthe object compound [I] or a salt thereof, preferably 10 mg to 100 mg onthe same basis, at the interval of 1 to 3 times a day. Typical unitdoses may be 5 mg, 10 mg, 20 mg, 50 mg, 100 mg and the like, althoughthese are only examples and not limitative, of course.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

PREPARATION 1

A mixture of 2-acetylamino-4-hydroxymethylthiazole (7.0 g) andN-chlorosuccinimide (6.5 g) in acetic acid (70 ml) was heated at 40° C.for 3.5 hours with stirring. The reaction mixture was concentrated underreduced pressure and the residue was added the aqueous sodiumbicarbonate. The mixture was extracted with a mixture of ethyl acetateand tetrahydrofuran (1:1), washed with water and dried over magnesiumsulfate. The solvent was concentrated under reduced pressure and theresidue was triturated with isopropyl ether. The precipitates werecollected by filtration, washed with isopropyl ether and dried in vacuoto give 2-acetylamino-5-chloro-4-hydroxymethylthiazole (7.3 g, yield :78.5%). mp: 145°-146° C. IR (Nujol) : 3150, 1690, 1550, 1285 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.17 (3H, s), 4.17 (2H, d, J=5 Hz), 5.17(1H, t, J=5 Hz) Mass: M⁺² 208, M+1 207, M 206, m/e 164, 147, 135

PREPARATION 2

A mixture of 2-amino-4-methylthiazole hydrochloride 1.5 g) andN-chlorosuccinimide (1.6 g) in acetic acid (15 ml) was heated 40° C. for5.5 hours with stirring. The reaction mixture was poured into ice waterand the solution was adjusted to pH 8.5 using sodium bicarbonate. Themixture was extracted with a mixture of tetrahydrofuran and ethylacetate (1:1), washed with aqueous saturated sodium chloride and driedover magnesium sulfate. The solvent was concentrated under reducedpressure to give 2-amino-5-chloro-4-methylthiazole (1.4 g, yield: 94.6%,oil).

NMR (DMSO-d₆, 200 MHZ, ppm): 2.09 (3H, s), 7.00 (2H, br s) Mass: M⁺²150, M⁺¹ 149, M 148, m/e 133, 113, 99

PREPARATION 3

To a solution of 2-amino-4-methylthiazole hydrochloride (3.0 g) inacetic acid (20 ml) was added once N-bromosuccinimide (4.0 g) at roomtemperature with stirring. The mixture was stirred at room temperaturefor 1.5 hours and the reaction mixture was poured into isopropyl etherunder ice cooling. The precipitates were collected by filtration, washedwith ethyl ether and dried in vacuo to give2-amino-5-bromo-4-methylthiazole hydrochloride (4.1 g, yield: 89.1%).

mp: 175°-178° C. (dec.) IR (Nujol): 3200, 2500-2700, 1635 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm) : 2.14 (3H, s), 8.90 (3H, br s)

Mass: M⁺³ 196, M⁺² 195, M⁺¹ 194, M 193, m/e 192, 191, 149, 123, 113

EXAMPLE 1

A solution of 1-acetyl-2-(4-nitrophenyl)ethane (9.6 g) and pyridiniumbromide perbromide (18 g) in acetic acid and 35% hydrogen bromide inacetic acid (21 ml) was stirred at room temperature for 5 hours. Thereaction mixture was washed with isopropyl ether and decanted. To theresidue was added the thiourea (6 g), sodium acetate (8 g) and ethanol(150 ml). The mixture was heated at 50° C. for 2 hours with stirring.The reaction mixture was concentrated in vacuo and to the residue wasadded water and then the mixture was adjusted to pH 8. The solution wasextracted with ethyl acetate and washed with 10% aqueous hydrochloricacid and dried over magnesium sulfate. The solvent was concentrated invacuo and the residue was subjected to column chromatography on silicagel (silica gel 60, 70-230 mesh; Merck: 300 g) and eluted with a mixtureof chloroform and methanol (10:1). The fractions containing theobjective compound were combined and concentrated under reduced pressureto give 2-amino-4-methyl-5-(4-nitrobenzyl)thiazole (2.0 g, yield:16.2%).

IR (Nujol): 3200, 3250, 3350, 1630, 1605, 1515, 1350 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 2.20 (3H, s), 4.10 (2H, s), 7.50 (2H, d, J=9Hz), 8.16 (2H, d, J=9 Hz), 8.85 (2H, s) Mass: M⁺¹ 250, M 249, m/e 234,204, 190, 127

EXAMPLE 2

To a solution of potassium permanganate (4 g) in water (400 ml) wasportionwise added the 2-amino-4-methyl-5-(4-nitrobenzyl)thiazole (2.3 g)at 80°-90° C. with stirring. The mixture was refluxed for 2 hours withstirring. The reaction mixture was filtered and then the filtrate wasadjusted to pH 2.0 using diluted aqueous hydrochloric acid under icecooling. The precipitates were collected by filtration, washed withwater and dried in vacuo to give 2-amino-5-(4-nitrobenzoyl)-4-thiazolecarboxylic acid (1.50 g, yield: 75.0%).

IR (Nujol): 3500, 2650, 2550, 1710, 1690, 1605, 1525, 1350 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.70 (2H, s), 8.25 (2H, d, J=10 Hz), 8.43(2H, d, J=10 Hz) Mass: M 293, m/e 192, 167

EXAMPLE 3

A mixture of 2-amino-5-(4-nitrobenzoyl)-4-thiazolecarboxylic acid (2.6g) and 10% palladium on carbon (1 g, 50% wet) in a mixture of methanol(50 ml) and tetrahydrofuran (50 ml) was hydrogenated under atmosphericpressure for 2 hours. The reaction mixture was filtered and then thefiltrate was concentrated under reduced pressure. The residue wastriturated with ether and the precipitates were collected by filtration,washed with ether and dried in vacuo to give2-amino-5-(4-aminobenzoyl)-4-thiazolecarboxylic acid (2.10 g, yield:90.0%).

mp: 290°-295° C. (dec.)

IR (Nujol): 3470, 3370, 2700-2500, 1690-1660, 1600 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 5.73 (2H, br s), 6.80 (2H, d, J=10 Hz), 6.80(2H, br s), 7.70 (2H, d, J=10 Hz) Mass: m/e 220, 205, 151, 137, 120

EXAMPLE 4

A mixture of chloromethyl-(4-nitrophenyl)diketone (2 g), thiourea (1.5g) and sodium acetate (1.6 g) in ethanol (20 ml) was heated at 50° C.for 4 hours with stirring. The mixture was concentrated in vacuo and theresidue was triturated with water. The precipitates were collected byfiltration, washed with water and dried in vacuo to give solid. Thesolid was subjected to column chromatography on silica gel (silica gel60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroformand methanol (10:1). The fractions containing the objective compoundwere combined and concentrated under reduced pressure to give2-amino-4-(4-nitrobenzoyl)thiazole (0.71 g, yield: 32.4%). mp: 194°-198°C. (dec.) IR (Nujol): 3300-3450, 1660, 1600, 1520, 1350 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 7.30 (2H, s), 7.60 (1H, s), 8.15 (2H, d, J=9Hz), 8.30 (2H, d, J=9 Hz) Mass: M⁺¹ 250, M 249, m/e 219, 205, 150, 99

EXAMPLE 5

A mixture of 2-amino-4-(4-nitrobenzoyl)thiazole (0.7 g) and 10%palladium on carbon (1 g, 50% wet) in a mixture of tetrahydrofuran (50ml), methanol (50 ml) and acetic acid (5 ml) was hydrogenated underatmospheric pressure for 7 hours. The reaction mixture was filtered andthen, the filtrate was concentrated under reduced pressure. The residuewas dissolved in water and adjusted to pH 8.0 using aqueous sodiumbicarbonate. The precipitates were collected by filtration, washed withwater and dried in vacuo to give 2-amino-4-4-aminobenzoyl)thiazole (0.54g, yield: 87.7%). mp: 180°-184° C. (dec.) IR (Nujol): 3150, 3350, 3450,1620, 1595 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 6.00 (2H, s), 6.55 (2H, d, J=9 Hz), 7.10(2H, s), 7.25 (1H, s), 7.93 (2H, d, J=9 Hz) Mass: M⁺¹ 220, M 219, m/e205, 160, 120

EXAMPLE 6

A mixture of 2-amino-4-(4-aminobenzoyl)thiazole (6 g) and methoxyaminehydrochloride (13 g) in methanol (800 ml) was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated underreduced pressure and then to the residue was added water. The solutionwas adjusted to pH 8.5 using 10% aqueous sodium bicarbonate underice-cooling. The precipitates were collected by filtration, washed withwater and recrystallized from ethanol to give2-amino-4-[(4-aminophenyl)methoxyiminomethyl]thiazole (4.9 g, yield:72.1%). mp: 181°-183° C. IR (Nujol): 3350, 3100, 1605, 1510, 1380 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 3.73 (3H, s), 5.29 (2H, s), 6.46 (2H, d, J=9Hz), 6.95 (1H, s), 7.00 (2H, d, J=9 Hz) Mass: M⁺¹ 249, M 248, m/e 217,203

EXAMPLE 7

To a mixture of 2-amino-5-(4-nitrophenylsulfonyl)thiazole (4.0 g) andammonium chloride in a mixture of ethanol (80 ml), tetrahydrofuran (40ml) and water (30 ml) was portionwise added the iron powder (4 g) at 80°C. with stirring. The mixture was refluxed for 1.5 hours with stirring.The reaction mixture was filtered by suction and the filtrate wasconcentrated under reduced pressure. The residue was triturated withwater and the precipitates were collected by filtration, washed withwater and dried in vacuo to give2-amino-5-(4-aminophenylsulfonyl)thiazole (3.10 g, yield: 86.6%). mp:218°-219° C. IR (Nujol): 3400, 3300, 1620, 1595, 1535, 1380 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 6.07 (2H, s), 6.57 (2H, d, J=9 Hz), 7.43(2H, d, J=9 Hz), 7.40 (1H, s), 7.77 (2H, s) Mass: M⁺¹ 256, M 255, m/e191, 140

EXAMPLE 8

A mixture of 2-acetylamino-4-chloromethylthiazole (1.9 g),4-nitrothiophenol (1.6 g) and potassium carbonate (2.0 g) in aN,N-dimethylformamide (50 ml) was heated at 100° C. for 3 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration, washed with water and dried in vacuo to give2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (2.95 g, yield:95.5%). mp: 165°-166° C.

IR (Nujol): 3150, 1655, 1595, 1545, 1500, 1335, 1290 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.17 (3H, s), 4.67 (2H, s), 7.15 (1H, s),7.60 (2H, d, J=8 Hz), 8.17 (2H, d, J=8 Hz) Mass: M⁺¹ 310, M 309, m/e267, 246, 155, 124, 113

EXAMPLE 9

To a mixture of 2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (11 g)and ammonium chloride (2 g) in a mixture of tetrahydrofuran (200 ml),ethanol (200 ml) and water (100 ml) was added portionwise the ironpowder (17 g) at 80° C. with stirring. The mixture was refluxed for 3hours with stirring. The reaction mixture was filtered by suction andthe filtrate was concentrated under reduced pressure and then theresidue was triturated with water. The precipitates were collected byfiltration, washed with water and dried in vacuo to give2-acetylamino-4-(4-aminophenylthiomethyl)thiazole (9.3 g, yield: 93.6%).

IR (Nujol): 3400, 3250, 3150, 1690, 1545, 1370, 1220 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 2.10 (3H, s), 3.90 (2H, s), 5.20 (2H, s),6.50 (2H, d, J=8 Hz), 6.70 (1H, s), 7.05 (2H, d, J=8 Hz), 12.10 (1H, s)Mass: M⁺¹ 280, M 279, m/e 236, 220, 216, 205

EXAMPLE 10

To a solution of 2-acetylamino-4-(4-aminophenylthiomethyl)thiazole (9.0g) in ethyl acetate (300 ml) was added portionwise the3-chloroperbenzoic acid (17 g) at 5° C. with stirring. The mixture wasstirred at room temperature for 16 hours. The reaction mixture waswashed with aqueous sodium bicarbonate and dried over magnesium sulfate.The solvent was concentrated under reduced pressure to give solid. Thesolid was subjected to column chromatography on silica gel (silica gel60, 70-230 mesh; Merck: 300 g) and eluted with a mixture of chloroformand methanol (10:1). The fractions containing the objective compoundwere combined and concentrated under reduced pressure to give2-acetylamino-4-(4-aminophenylsulfonylmethyl)thiazole (4.85 g, yield:48.3%). mp: 135°-137° C.

IR (Nujol): 3450, 3350, 3200, 1680, 1635, 1595, 1550, 1300 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.17 (3H, s), 4.50 (2H, s), 6.17 (2H, s),6.63 (2H, d, J=8 Hz), 6.90 (1H, s), 7.35 (2H, d, J=8 Hz)

EXAMPLE 11

A solution of 2-acetylamino-4-[4-aminophenylsulfonylmethyl)thiazole (4.8g) in a mixture of acetic acid (35 ml) and 6N-aqueous hydrochloric acid(10 ml) was refluxed for 2.5 hours with stirring. The reaction mixturewas poured into ice-water and then the solution was adjusted to pH 8.0using 10% aqueous sodium bicarbonate with stirring. The precipitateswere collected by filtration, washed with water and dried in vacuo togive 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.50 g, yield:60.2%). mp: 203°-206° C. (dec.) IR (Nujol): 3450, 3350, 1630, 1595, 15301380 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.20 (2H, s), 6.03 (2H, s), 6.27 (1H, s),6.57 (2H, d, J=8 Hz), 6.85 (2H, s), 7.33 (2H, d, J=8 Hz) Mass: M 269,m/e 205, 162, 140, 113

EXAMPLE 12

A mixture of 4-nitrothiophenol (9.3 g), 2-amino-4-chloromethylthiazolehydrochloride (11 g) and potassium carbonate (20 g) inN,N-dimethylformamide (200 ml) was heated at 85°-90° C. for 5 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration, washed with water and dried in vacuo to give2-amino-4-[4-nitrophenylthiomethyl)thiazole (15.80 g, yield: 98.6%). IR(Nujol): 3400, 3100, 1630, 1530, 1340 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.23 (2H, s), 6.60 (1H, s), 7.03 (2H, s),7.63 (2H, d, J=9 Hz), 8.20 (2H, d, J=9 Hz) Mass: M⁺¹ 268, M 267, m/e237, 177, 113

EXAMPLE 13

To a mixture of 2-amino-4-(4-nitrophenylthiomethyl)thiazole (15 g) andammonium chloride (2 g) in a mixture of tetrahydrofuran (100 ml),ethanol (150 ml) and water was added portionwise added the iron powder(15 g) at 80° C. with stirring. The mixture was refluxed for 2 hourswith stirring. The reaction mixture was filtered by suction and thefiltrate was concentrated under reduced pressure. The residue wasextracted with a mixture of tetrahydrofuran and ethyl acetate (1:1),washed with saturated aqueous sodium chloride and dried over magnesiumsulfate. The solvent was evaporated in vacuo and the residue wastriturated with chloroform. The precipitates were collected byfiltration, washed with ether and dried in vacuo to give2-amino-4-(4-aminophenylthiomethyl)thiazole (10.50 g, yield: 73.0%). mp:130°-132° C.

IR (Nujol): 3425, 3350, 1630, 1605, 1595, 1535, 1495, 1440, 1380, 1340,1280 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 3.70 (2H, s), 5.15 (2H, s), 6.10 (1H, s),6.45 (2H, d, J=9 Hz), 6.83 (2H, s), 7.00 (2H, d, J=9 Hz) Mass: M⁺¹ 238,M 237, m/e 204, 124, 113

EXAMPLE 14

A solution of 3-chloroperbenzoic acid (4.9 g) in dichloromethane (100ml) was dropwise added to a solution of2-amino-4-(4-aminophenylthiomethyl)thiazole (5.1 g) in a mixture ofdichloromethane (200 ml) and N,N-dimethylformamide (10 ml) at 5° C. withstirring. The mixture was stirred at 5° C. for 1.5 hours with stirring.The precipitates were collected by filtration, washed with ethyl acetateand dried in vacuo to give solid. The solid was recrystallized fromethanol to give 2-amino-4-(4-aminophenylsulfinylmethyl)thiazole (4.70 g,yield: 86.3%).

IR (Nujol): 3350-3100, 1620, 1600, 1500, 1380, 1300 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 3.87 (2H, s), 6.27 (2H, s), 6.67 (2H, d, J=9Hz), 7.00 (2H, s), 7.30 (2H, d, J=9 Hz), 7.67 (1H, s) Mass: M⁺¹ 254, M253, m/e 237, 205, 156, 139

EXAMPLE 15

To a solution of 2-amino-4-(4-aminophenylsulfinylmethyl)thiazole (2.8 g)in N,N-dimethylformamide (30 ml) was added portionwise the3-chloroperbenzoic acid (2.6 g) at 5° C. with stirring. The mixture wasstirred at room temperature for 2 hours and then the solution was pouredinto ice-water. The precipitates were collected by filtration, washedwith aqueous sodium bicarbonate, washed with water and dried in vacuo togive 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.85 g, yield95.6%). mp: 204°-208° C. (dec.)

IR (Nujol): 3375, 3275, 3150, 1615, 1595, 1295, 1140 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.30 (2H, s), 6.10 (2H, s), 6.30 (1H, s),6.67 (2H, d, J=8 Hz), 6.95 (2H, s), 7.43 (2H, d, J=8 Hz) Mass: M 269,m/e 220, 205

EXAMPLE 16

A mixture of 2-acetylamino-5-chlorothiazole (5 g), 4-nitrothiophenol(4.83 g) and potassium carbonate (7.8 g) in N,N-dimethylformamide (100ml) was heated at 120° C. for 3 hours with stirring. The reactionmixture was poured into ice-water. The precipitates were collected byfiltration, washed with water and dried in vacuo to give solid. Thesolid was subjected to column chromatography on silica gel (silica gel60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of n-hexane andethyl acetate (3:1). The fractions containing the objective compoundwere combined and concentrated under reduced pressure to give2-acetylamino-5-(4-nitrophenylthio)thiazole (3.74 g, yield: 50.2%). mp:250°-255° C. (dec.)

IR (Nujol): 3150, 1695, 1595, 1550, 1505, 1340, 1300, 1230 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.23 (3H, s), 7.40 (2H, d, J=8 Hz), 7.90(1H, s), 8.23 (2H, d, J=8 Hz), 12.43 (1H, br s) Mass: M⁺¹ 296, M 295,m/e 265, 253, 223, 181, 166

EXAMPLE 17

To a mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (2.8 g) andammonium chloride (0.3 g) in a mixture of ethanol (60 ml), water (30 ml)and tetrahydrofuran (20 ml) was portionwise added the iron powder (3 g)at 80° C. with stirring. The mixture was refluxed for 2.5 hours withstirring. The reaction mixture was filtered by suction and the filtratewas concentrated under reduced pressure. The residue was triturated withwater, the precipitates were collected by filtration, washed with waterand dried in vacuo to give 2-acetylamino-5-(4-aminophenylthio)thiazole(2.0 g, yield: 79.5%). mp: 255°-257° C. (dec.)

IR (Nujol): 3450, 3375, 1680, 1620, 1595, 1380, 1300 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.17 (3H, s), 5.40 (2H, s), 6.60 (2H, d, J=9Hz), 7.20 (2H, d, J=9 Hz), 7.58 (1H, s), 12.15 (1H, s) Mass: M⁺¹ 266, M265, m/e, 223, 191, 181

EXAMPLE 18

A solution of 2-acetylamino-5-(4-aminophenylthio)thiazole (2.5 g) in amixture of acetic acid (20 ml) and 6N-aqueous hydrochloric acid (5 ml)was refluxed for 4 hours with stirring. The reaction mixture was pouredinto ice-water and the solution was adjusted to pH 10 using 1N-aqueoussodium hydroxide with stirring under ice cooling. The precipitates werecollected by filtration, washed with water and dried in vacuo to give2-amino-5-(4-aminophenylthio)thiazole (1.70 g, yield: 81.5%).

IR (Nujol): 3400, 3300, 3150, 1630, 1600, 1515, 1380 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 5.27 (2H, s), 6.60 (2H, d, J=9 Hz), 7.10(2H, d, J=9 Hz), 7.17 (1H, s), 7.27 (2H, s) Mass: M⁺¹ 224, M 223, m/e191, 164, 136, 125

EXAMPLE 19

To a solution of 2-amino-5-(4-aminophenylthio)thiazole (4.0 g) in amixture of chloroform (140 ml) and N,N-dimethylformamide (20 ml) wasdropwise added the solution of 3-chloroperbenzoic acid (4.65 g) inchloroform (50 ml) at 5° C. with stirring. The mixture was stirred at 5°C. for 4 hours. The precipitates were collected by filtration, washedwith 10% aqueous sodium bicarbonate and water. The solid was dried invacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (3.75 g, yield:87.5%). mp: 173°-175° C.

IR (Nujol): 3500, 3350, 3225, 1640, 1595, 1525, 1380, 1320, 1225 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 5.67 (2H, s), 6.97 (2H, d, J=9 Hz), 7.23(2H, d, J=9 Hz), 7.50 (1H, s), 7.62 (2H, s) Mass: M⁺¹ 240, M 239, m/e223, 191, 147, 140

EXAMPLE 20

To a solution of 2-acetylamino-5-(4-aminophenylthio)thiazole (6.6 g) ina mixture of dichloromethane (300 ml) and N,N-dimethylformamide (50 ml)was dropwise added the solution of 3-chloroperbenzoic acid (5.9 g) indichloromethane (100 ml) at 5° C. with stirring. The mixture was stirredat 5° C. for 2 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was poured into 10%aqueous sodium bicarbonate. The solution was extracted with a mixture oftetrahydrofuran and ethyl acetate (1:1), washed with saturated aqueoussodium chloride and dried over magnesium sulfate. The solvent wasconcentrated under reduced pressure to give2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g, yield: 71.1%).mp: 194°-196° C. (dec.)

IR (Nujol): 3350, 3175, 1710, 1630, 1695, 1550, 1380, 1300, 1230 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.17 (3H, s), 5.80 (2H, br s), 6.70 (2H, d,J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.9 (1H, s) Mass: M⁺¹ 282, M 281, m/e265, 234, 222, 191

EXAMPLE 21

A mixture of 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g) ina mixture of aqueous 6N-hydrochloric acid (10 ml) and acetic acid (35ml) was refluxed for 3.5 hours with stirring. The reaction mixture wasdiluted with water and adjusted to pH 8 using aqueous sodium carbonateunder ice cooling. The precipitates were collected by filtration, washedwith water and dried in vacuo to give2-amino-5-(4-aminophenylsulfinyl)thiazole (4.5 g, yield: 100%). mp:205°-208° C. (dec.)

NMR (DMSO-d₆, 60 MHZ, ppm): 5.27 (2H, s), 6.55 (2H, d, J=8 Hz), 6.67(2H, d, J=8 Hz), 7.17 (1H, s), 7.42 (2H, s) Mass: m/e 223, 191, 124, 99

EXAMPLE 22

A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 4-mercaptopyridine(3.4 g) and potassium carbonate in N,N-dimethylformamide (50 ml) washeated at 120° C. for 2.5 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was triturated withwater. The precipitates were collected by filtration, washed with waterand dried in vacuo to give 2-acetylamino-5-(4-pyridylthio)thiazole (6.3g, yield: 83.7%). IR (Nujol): 3150, 1680, 1580, 1300 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 2.23 (3H, s), 7.10 (2H, d, J=6 Hz), 7.80(1H, s), 8.40 (2H, d, J=6 Hz), 11.90 (1H, br s)

EXAMPLE 23

A mixture of 2-acetylamino-5-(4-pyridylthio)thiazole (4.7 g), aceticacid (35 ml) and 6N-aqueous hydrochloric acid (10 ml) was refluxed for 2hours with stirring. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in water. The solution wasadjusted pH 8.5 using aqueous sodium bicarbonate under ice cooling. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give 2-amino-5-(4-pyridylthio)thiazole (2.7 g, yield:69.5%). mp: 180°-185° C. (dec.) IR (Nujol): 3270, 3150, 1630, 1580, 1380cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 7.13 (2H, d, J=6 Hz), 7.30 (1H, s), 7.60(2H, s), 8.40 (2H, d, J=6 Hz) Mass: M⁺¹ 210, M 209, m/e 188, 150, 131,99

EXAMPLE 24

To a mixture of 2-amino-5-(4-pyridylthio)thiazole (4.0 g) in a mixtureof chloroform (300 ml) and N,N-dimethylformamide (10 ml) was addeddropwise the solution of 3-chloroperbenzoic acid (4.5 g) in chloroform(100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 26hours under ice cooling. The reaction mixture was washed with aqueoussodium bicarbonate and water and dried over magnesium sulfate. Thesolvent was concentrated under reduced pressure to give solid. The solidwas subject to column chromatography on silica gel (silica gel 60,70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform andmethanol (10:1). The fractions containing the objective compound werecombined and concentrated under reduced pressure to give2-amino-5-(4-pyridylsulfinyl)thiazole (2.5 g, yield: 58.1%). mp:193°-195° C.

IR {Nujol): 3350, 3250, 1610, 1575, 1525, 1280, 1220 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.62 (2H, d, J=6 Hz), 7.87 (1H, s), 7.97(2H, s), 8.80 (2H, d, J=6 Hz) Mass: M 225, m/e 209, 177, 147, 131

EXAMPLE 25

A mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (4.0 g) in amixture of acetic acid (30 ml) and aqueous 6N hydrochloric acid (9 ml)was refluxed for 3 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 8.5 using aqueous sodiumbicarbonate. The precipitates were collected by filtration, washed withwater and dried in vacuo to give 2-amino-5-(4-nitrophenylthio)thiazole(2.6 g, yield: 76.5%). mp: 162°-164° C.

IR (Nujol): 3420, 3270, 1680, 1595, 1580, 1530, 1335, 1215 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.30 (2H, d, J=8 Hz), 7.40 (1H, s), 7.50(2H, s), 8.20 (2H, d, J=8 Hz) Mass: M⁺¹ 254, M 253, m/e 223, 191, 164,149, 121, 99

EXAMPLE 26

To a mixture of 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g) andpyridine (1 g) in N,N-dimethylformamide (30 ml) was added dropwise thepropionylchloride (1.1 g) at 5° C. under ice cooling with stirring. Themixture was stirred at 5° C. for 3.5 hours. The reaction mixture waspoured into ice water and the mixture was adjusted to pH 8 using aqueoussodium bicarbonate. The precipitates were collected by filtration,washed with water and dried in vacuo to give2-propionylamino-5-(4-nitrophenylthio)thiazole (2.5 g, yield: 78.7%).mp: 227°-229° C. (dec.)

IR (Nujol): 3150, 1710, 1595, 1580, 1555, 1505, 1340, 1180 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 1.20 (3H, t, J=8 Hz), 2.6 (2H, q, J=8 Hz),7.45 (2H, d, J=8 Hz), 7.92 (1H, s), 8.23 (2H, d, J=8 Hz) Mass: M⁺¹ 310,M 309, m/e 280, 252, 222

EXAMPLE 27

To a mixture of 2-propionylamino-5-(4-nitrophenylthio)thiazole (3 g),and ammonium chloride (1 g) in a mixture of ethanol (100 ml), water (30ml) and tetrahydrofuran (70 ml) was portionwise added the iron powder at80° C. with stirring. The mixture was refluxed for 2 hours withstirring. The reaction mixture was filtered by suction and the filtratewas concentrated under reduced pressure. The residue was triturated withwater, the precipitates were collected by filtration and washed withwater to give solid. The solid was recrystallized from ethanol to give2-propionylamino-5-(4-aminophenylthio)thiazole (2.6 g, yield: 96.3%).mp: 185°-187° C.

NMR (DMSO-d₆, 60 MHZ, ppm): 1.30 (3H, t, J=7 Hz), 2.50 (2H, q, J=7 Hz),5.50 (2H, br s), 6.60 (2H, d, J=8 Hz), 7.23 (2H, d, J=8 Hz), 7.60 (1H,s) Mass: M⁺¹ 280, M 279, m/e 264, 250, 222, 205

EXAMPLE 28

A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 2-mercaptopyridine(3.5 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml)was heated at 130° C. for 3.5 hours with stirring. The reaction mixturewas concentrated under reduced pressure and the residue was trituratedwith water. The precipitates were collected by filtration, washed withwater and dried in vacuo to give 2-acetylamino-5-(2-pyridylthio)thiazole(5.70 g, yield: 76.0%). mp: 185°-188° C. (dec.)

IR (Nujol): 3150, 1695, 1575, 1300, 1280, 1230 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.20 (3H, s), 7.00-7.40 (2H, m), 7.70-7.90(2H, m), 8.50 (1H, m), 12.40 (1H, s) Mass: M⁺¹ 252, M 251, m/e 209, 176,167

EXAMPLE 29

A mixture of 2-acetylamino-5-(2-pyridylthio)thiazole (5.0 g) in amixture of acetic acid (50 ml) and aqueous 6N-hydrochloric acid (10 ml)was refluxed for 2 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 8.5 using aqueous sodiumbicarbonate, and then the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and dried over magnesium sulfate.The solvent was concentrated under reduced pressure and the residue wastriturated with a solution of hydrochloric acid in ethanol. Theprecipitates were collected by filtration, washed with isopropyl etherand dried in vacuo to give 2-amino-5-(2-pyridylthio)thiazoledihydrochloride (4.60 g, yield: 85.8%). mp: 220°-225° C. (dec.) IR(Nujol ): 2550-2300, 1620, 1595 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.20-7.60 (2H, m), 7.70-8.00 (4H, m), 8.55(1H, m), 10.50 (3H, br s) Mass: m/e 209 (free), 187, 167, 123

EXAMPLE 30

To a solution of 2-amino-5-(2-pyridylthio)thiazole dihydrochloride (4.0g) in chloroform (100 ml) was dropwise added the solution of3-chloroperbenzoic acid (5.0 g) in chloroform (100 ml) at 5° C. withstirring. The mixture was stirred at 5° C. for 1.5 hours. The reactionmixture was washed with aqueous sodium bicarbonate and dried overmagnesium sulfate. The solvent was concentrated under reduced pressureto give solid. The solid was subjected to column chromatography onsilica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with amixture of chloroform and methanol (10:1). The fractions containing theobjective compound were combined and concentrated under reduced pressureto give 2-amino-5-(2-pyridylsulfinyl)thiazole (3.4 g, yield: 78.9%). mp:200°-202° C. (dec.) IR (Nujol): 3300, 3150, 1630, 1575, 1270, 1225 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 7.40-7.60 (1H, m), 7.70 (1H, s), 7.73 (2H,s), 7.90-8.20 (2H, m), 8.60 (1H, m) Mass: M 225, m/e 209, 147, 115

EXAMPLE 31

To a solution of 2-amino-5-(2-pyridylthio)thiazole (5.7 g) in chloroform(450 ml) was dropwise added the solution of 3-chloroperbenzoic acid (15g) in chloroform (100 ml) at 5° C. with stirring. The mixture wasstirred at room temperature for 16 hours. The reaction mixture waswashed with aqueous sodium bicarbonate and dried over magnesium sulfate.The solvent was concentrated under reduced pressure to give2-amino-5-(2-pyridylsulfonyl)thiazole (2.2 g, yield: 33%). mp: 178°-182°C. (dec.)

IR (Nujol): 3375, 3300, 3150, 1645, 1610, 1525, 1320, 1220 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.55-7.80 (2H, m), 8.00-8.30 (4H, m), 8.77(1H, m) Mass: M⁺¹ 242, M 241, m/e 177, 156, 135

EXAMPLE 32

A mixture of 2-acetamido-5-chlorothiazole (14.3 g), 2-mercaptopyrimidine(10 g) and potassium carbonate anhydrous (22.4 g) inN,N-dimethylformamide (280 ml) was stirred at 150° C. an hour. Thereaction mixture was poured into water with stirring under ice cooling.The mixture was extracted with ethyl acetate, washed with water anddried over magnesium sulfate. The organic layer was concentrated underreduced pressure to give solid. The solid was triturated with water, andthe precipitates were collected by filtration, washed with water anddried in vacuo to give 2-acetamido-5-(2-pyrimidinylthio)thiazole (12.30g, yield: 60.2%). mp: 225° C. (dec.) IR (Nujol): 3170, 1645, 1555, 1310cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.20 (3H, s), 7.33 (1H, t, J=4Hz), 7.70 (1H,s), 8.68 (2H, d, J=4Hz), 12.33 (1H, br s) Mass: M⁺² 254, M⁺¹ 253, M 252,m/e 210, 168

EXAMPLE 33

Starting from 2-acetamido-5-(2-pyrimidinylthio)thiazole,2-amino-5-(2-pyrimidinylthio)thiazole (2.02 g, yield: 22.0%) wasobtained according to a similar manner to that of Example 40. mp:175°-177° C. IR (Nujol): 3270, 3100, 1655, 1565, 1555, 1540 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.13-7.57 (4H, m), 8.40-8.77 (2H, m) Mass:M⁺² 212, M⁺¹ 211, M 210, m/e 168, 124

EXAMPLE 34

A mixture of 2-acetylamino-5-chlorothiazole (5.3 g),1-methyl-2-mercaptoimidazole (3.6 g) and potassium carbonate (6.2 g) inN,N-dimethylformamide (50 ml) was heated at 130° C. for 5.5 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration washed with water and dried in vacuo to give2-acetylamino-5-(1-methylimidazol-2-ylthio)thiazole (6.95 g, yield:91.2%). mp: 155°-160° C. (dec.) IR (Nujol): 3400, 1690, 1565, 1300 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 2.10 (3H, s), 3.70 (3H, s), 6.90 (1H, s),7.26 (1H, s), 7.60 (1H, s) Mass: M⁺¹ 255, M 254, m/e 212, 179, 170, 114

EXAMPLE 35

A solution of 2-acetylamino-5-(1-methylimidazol-2-ylthio)thiazole (7.0g) in a mixture of acetic acid (100 ml) and aqueous 6N-hydrochloric acid(20 ml) was refluxed for 3.5 hours with stirring. The reaction mixturewas concentrated under reduced pressure and the residue was adjusted topH 8 using aqueous sodium bicarbonate under ice cooling. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give 2-amino-5-(1-methylimidazol-2-ylthio)thiazole (4.9 g,yield: 83.9%). mp: 180°-190° C. (dec.) IR (Nujol): 3300, 3150, 1620,1530, 1280, 1220 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 3.77 (3H, s), 7.03 (1H, s), 7.25 (1H, s),7.37 (1H, s) Mass: M⁺¹ 213, M 212, m/e 179, 170, 126, 114

EXAMPLE 36

A solution of 2-acetamido-5-(4-aminophenylthio)thiazole (3.2 g) inpyridine (64 ml) was added methanesulfonyl chloride (1.52 g) at 5° C.with stirring. The reaction mixture was stirred for 3 hours at 5° C. andconcentrated in vacuo to give solid. The solid was subject to columnchromatography on silica gel (silica gel, 70-230 mesh; Merck: 200 g) andeluted with a mixture of chloroform and methanol (50:1) and eluted witha mixture of chloroform and methanol (20:1). The fractions containingthe objective compound were combined and evaporated to dryness in vacuoto give 2-acetamido-5-(4-methanesulfonylaminophenylthio)thiazole (4.0 g,yield: 96.6%). mp: 236°-239° C.

IR (Nujol): 3250, 3150, 1695, 1565, 1495, 1330 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.16 (3H, s), 3.30 (3H, s), 7.20-7.30 (5H,m), 7.73 (1H, s), 8.10 (1H, s) Mass: M⁺ 343, m;,e 342, 301, 264, 222

EXAMPLE 37

Starting from 2-acetamido-5-(4-methanesulfonylaminophenylthio)thiazole,2-amino-5-(4-methanesulfonylaminophenylthio)thiazole (2.28 g, yield:64.9%) was obtained according to a similar manner to that of Example 40.mp: 185°-187° C. IR (Nujol): 3430, 3260, 1610, 1510, 1320 cm⁻¹ NMR(DMSO-d₆, 60 MHZ, ppm): 3.00 (3H, s), 7.20-7.37 (5H, m), 7.47 (2H, brs), 9.76 (1H, br s) Mass: M⁺¹ 302, M⁺ 301, m/e 222, 190

EXAMPLE 38

To a mixture of 2-amino-5-(4-pyridylthio)thiazole (2.5 g) and pyridine(3 g) in N,N-dimethylformamide (25 ml) was added dropwise the4-fluorobenzoyl chloride (2.7 g) at 5° C. under ice cooling withstirring. The mixture was stirred at 5° C. for 4 hours under icecooling. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration, washed with water and dried in vacuo to give2-(4-fluorobenzoylamino)-5-(4-pyridylthio)thiazole (2.5 g, yield:63.1%). mp: 220°-225° C. (dec.)

IR (Nujol): 3150, 1670, 1605, 1587, 1550, 1295, 1230 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 7.10-7.67 (4H, m), 7.95 (1H, s), 8.10-8.60(4H, m), 12.85 (1H, s) Mass: M⁺¹ 332, M 331, m/e 209, 123, 95

EXAMPLE 39

A mixture of salt of potassium 2,4-difluorothiophenol (20 g),2-acetamido-5-chlorothiazole (21 g) and potassium carbonate anhydrous(29.8 g) in N,N-dimethylformamide (400 ml) was stirred at 130° C. for 7hours. The reaction mixture was concentrated under reduced pressure. Theresidue was triturated with water and the precipitates were collected byfiltration, washed with water and dried in vacuo to give solid. Thesolid was subjected to column chromatography on silica gel (silica gel,70-230 mesh; Merck: 750 g) and eluted with a mixture of chloroform andmethanol (50:1). The fractions containing the objective compound werecombined and evaporated to dryness in vacuo to give2-acetamido-5-(2,4-difluorophenylthio)thiazole (11.91 g, yield: 38.5%).mp: 156°-170° C. (dec.) IR (Nujol): 3160, 3060, 1695, 1585, 1560, 1295cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.20 (3H, s), 6.90-7.90 (4H, m), 12.27 (1H,br s) Mass: M 286, m/e 270, 243

EXAMPLE 40

A mixture of 2-acetamido-5-(2,4-difluorophenylthio)thiazole (14.8 g) ina mixture of ethanol (150 ml) and concentrated hydrochloric acid (15 ml)was refluxed for 1.5 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 12 using aqueous sodium hydroxidewith stirring under ice-cooling. The mixture was extracted with ethylacetate, washed with water and dried over magnesium sulfate. The organiclayer was concentrated under reduced pressure to give solid. The solidwas subjected to column chromatography on silica gel (silica gel,230-400 mesh, Nakarai) (300 g) and eluted with a mixture of chloroformand methanol (100:1). The fractions containing the objective compoundwere combined and evaporated to dryness in vacuo to give2-amino-5-(2,4-difluorophenylthio)thiazole (6.26 g, yield: 49.6%). mp:116°-117° C. IR (Nujol): 3410, 3090, 1625, 1600, 1515 cm⁻¹ NMR (DMSO-d₆,60 MHZ, ppm): 7.07-7.76 (6H, m) MASS: M⁺² 246, M 244, m/e 157

EXAMPLE 41

Starting from 2-amino-5-(2,4-difluorophenylthio)thiazole,2-amino-5-(2,4-difluorophenylsulfinyl)thiazole 2.37 g, yield: 65.4%) wasobtained according to a similar manner to that of Example 30. mp:171°-172° C. IR (Nujol): 3300, 3100, 1635, 1605, 1600 cm⁻¹ NMR (DMSO-d₆,90 MHZ, ppm): 7.23-8.00 (6H, m) Mass: M⁺ 260, m/e 244, 212

EXAMPLE 42

A mixture of 4-chloromethyl-2-formylaminothiazole (1.86 g),4-mercaptopyridine (1.23 g) and potassium carbonate (1.8 g) inN,N-dimethylformamide (20 ml) was heated at 100° C. for 2 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration, washed with water and dried in vacuo to give2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.7 g, yield: 68.0%). mp:182°-184° C. IR (Nujol): 1675, 1650, 1585, 1560, 1270 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.30 (2H, s), 7.15 (1H, s), 7.33 (2H, d,J=6Hz), 8.33 (2H, d, J=6Hz), 8.45 (1H, s) Mass: M⁺¹ 252, M 251, m/e 223,155, 141, 113

EXAMPLE 43

A mixture of 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.6 g) andN-chlorosuccinimide (1.5 g) in acetic acid (25 ml) was heated at 40°-50°C. for 5 hours with stirring and then the mixture was allowed to standat room temperature for 16 hours. The reaction mixture was concentratedunder reduced pressure and the residue was triturated with aqueoussodium bicarbonate. The precipitates were collected by filtration washedwith water and dried in vacuo to give5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (0.85 g, yield:46.8%). mp: 200°-203° C. (dec.) IR (Nujol): 1680, 1665, 1587, 1300 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.37 (2H, s), 7.40 (2H, d, J=6Hz), 7.47 (2H,d, J=6Hz), 8.53 (1H, s), 12.50 (1H, s)

Mass: M⁺³ 288, M⁺² 287, M⁺¹ 286, M 285, m/e 256, 250, 175, 147

EXAMPLE 44

A solution of 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole(4.9 g) in a mixture of ethanol (25 ml), tetrahydrofuran (20 ml) andconcentrated hydrochloric acid (7 ml) was stirred at room temperaturefor 4 hours. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in water. The solution wasadjusted to pH 8 using aqueous sodium bicarbonate under ice-cooling. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give 2-amino-5-chloro-4-(4-pyridylthiomethyl)thiazole (0.26g, yield: 56.6%). IR (Nujol): 3350, 3250, 1685, 1530 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.13 (2H, s), 7.33 (2H, d, J=6Hz), 7.43 (2H,s), 8.50 (2H, d, J=6Hz) Mass: M⁺² 259, M⁺¹ 258, M 257, m/e 220, 147, 111

EXAMPLE 45

A mixture of 4-chloromethyl-2-formylaminothiazole (1.76 g),4-nitrothiophenol (1.7 g) and potassium carbonate (1.8 g) inN,N-dimethylformamide (20 ml) was heated at 100° C. with stirring. Thereaction mixture was poured into ice-water and stirred at 5° C. for anhour. The precipitates were collected by filtration, washed with waterand dried in vacuo to give2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.3 g, yield: 78%).mp: 158°-160° C. IR (Nujol): 3500, 1680, 1595, 1550, 1330 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.40 (2H, s), 7.13 (1H, s), 7.56 (2H, d,J=8Hz), 8.10 (2H, d, J=8Hz), 8.50 (1H, s) Mass: M 295, m/e 265, 141, 113

EXAMPLE 46

To a mixture of 2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.2g) and ammonium chloride (0.5 g) in a mixture of tetrahydrofuran (30ml), ethanol (50 ml) and water (10 ml) was added portionwise the ironpowder at 80° C. with stirring. The mixture was refluxed for 2 hourswith stirring. The reaction mixture was filtered by suction and theresidue was triturated with water. The precipitates were collected byfiltration, washed with water and dried in vacuo to give2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g, yield: 81%).mp: 180°-182° C.

IR (Nujol): 3350, 3300, 1680, 1625, 1600, 1325, 1290 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.00 (2H, s), 5.23 (2H, s), 6.57 (2H, d,J=8Hz), 6.83 (1H, s), 7 10 (2H, d, J=8Hz), 8.50 (1H, s) Mass: M⁺¹ 266, M265, m/e 237, 205, 141, 124

EXAMPLE 47

A mixture of acetic anhydride (1.84 g) and formic acid (0.9 g) washeated at 50° C. for 0.5 hours with stirring. The solution was cooled atroom temperature and to the solution was added the2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g). The mixturewas stirred at room temperature for 6.5 hours and then the mixture waspoured into ice-water. The precipitates were collected by filtration,washed with water and dried in vacuo to give2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (1.7 g, yield:96.7%). mp: 195°-197° C. (dec.)

IR (Nujol): 3150, 1680, 1660, 1595, 1525, 1310, 1290 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.30 (2H, s), 7.10 (1H, s), 7.47 (2H, d,J=8Hz), 7.73 (2H, d, J=8Hz), 8.40 (1H, s), 8.60 (1H, s), 10.33 (1H, s),12.20 (1H, s) Mass: M⁺¹ 294, M 293, m/e 265, 153, 141, 113

EXAMPLE 48

To a solution of 2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole(2.9 g) in acetic acid (30 ml) was portionwise added N-chlorosuccinimideat 50° C. with stirring. The mixture was heated at 50° C. with stirring.The reaction mixture was concentrated under reduced pressure and theresidue was triturated with water. The mixture was extracted with amixture of ethyl acetate and tetrahydrofuran (1:1), washed with waterand dried over magnesium sulfate. The solvent was concentrated underreduced pressure to give solid. The solid was subjected to columnchromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g)and eluted with a mixture of chloroform and methanol (10:1). Thefractions containing the objective compound were combined andconcentrated under reduced pressure to give5-chloro-2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (2.0 g,yield: 61.2%). mp: 130°-150° C. (dec.) IR (Nujol): 3350, 3200, 1710,1690-1640, 1590 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 4.80 (2H, s), 7.26 (2H, d, J=8Hz), 7.56 (2H,d, J=8Hz), 8.25 (1H, s), 8.50 (1H, s), 10.23 (1H, s), 12.57 (1H, s)Mass: M 327, m/e 298, 292, 263, 234, 204

EXAMPLE 49

A solution of5-chloro-2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (3.5 g)in a mixture of concentrated hydrochloric acid (9 ml), methanol (30 ml)and tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours.The reaction mixture was concentrated under reduced pressure and theresidue was dissolved in water. The solution was adjusted to pH 8 usingaqueous sodium bicarbonate with stirring under ice cooling. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give solid. The solid was subjected to column chromatographyon silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted witha mixture of chloroform and methanol (10:1). The fractions containingthe objective compound were combined and concentrated under reducedpressure to give 2-amino-4-(4-aminophenylthiomethyl)-5-chlorothiazole(2.3 g, yield: 79.3%). mp: 158°-163° C. (dec.)

IR (Nujol): 3325, 3200, 3150, 1620, 1595, 1495, 1325, 1290 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 4.33 (2H, s), 5.50 (2H, br s), 6.60 (2H, d,J=8Hz), 7.10 (2H, d, J=8Hz), 7.25 (2H, br s) Mass: M 271, m/e 267, 236,221, 204, 124

EXAMPLE 50

A mixture of 2-acetylamino-5-chloro-4-hydroxymethylthiazole (1 g),4-mercaptopyridine (0.6 g) and potassium carbonate (1 g) inN,N-dimethylformamide (20 ml) was heated at 110° C. for 8 hours withstirring. The reaction mixture was poured into ice water and filtered bysuction. The filtrate was extracted with a mixture of ethyl acetate andtetrahydrofuran (1:1) and dried over magnesium sulfate. The solvent wasconcentrated under reduced pressure to give solid. The solid wassubjected to column chromatography on silica gel (silica gel 60, 70-230mesh; Merck: 75 g) and eluted with a mixture of chloroform and methanol(10:1). The fractions containing the objective compound were combinedand concentrated under reduced pressure to give2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole (0.90 g, yield:64.3%). mp: 220°-222° C. (dec.)

NMR (DMSO-d₆, 90 MHZ, ppm): 2.16 (3H, s), 4.40 (2H, d, J=6Hz), 5.13 (1H,t, J=6Hz), 7.05 (2H, d, J=6Hz), 8.30 (2H, d, J=6Hz), 12.43 (1H, s) Mass:M⁺¹ 282, M 281, m/e 239, 220, 205, 188

EXAMPLE 51

A mixture of 2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole(3.0 g) in a mixture of concentrated hydrochloric acid (8 ml) andethanol (100 ml) was refluxed for 2.5 hours with stirring. The reactionmixture was concentrated under reduced pressure and the residue wastriturated with acetone. The precipitates were collected by filtration,washed with isopropyl ether and were recrystallized from a mixture ofethanol and isopropyl ether to give2-amino-4-hydroxymethyl-5-(4-pyridylthio)thiazole dihydrochloride (2.5g, yield: 75.3%). mp: 231°-237° C. (dec.) IR (Nujol) 3350, 2300, 1610,1560 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 4.30-4.55 (3H, m), 7.80 (2H, d, J=6Hz), 8.65(2H, d, J=6Hz), 8.83 (4H, br s) Mass: M 239, m/e 222, 210, 188

EXAMPLE 52

Starting from 2-amino-5-(4-pyridylthio)thiazole2-amino-5-(4-pyridylsulfonyl)thiazole (0.73 g, yield: 17.1%) wasobtained according to a similar manner to that of Example 31. mp: 217°C. (dec.) IR (Nujol): 3260, 3100, 1620, 1580, 1525 cm⁻¹

NMR (DMSO-d₆, 90 MHZ, ppm): 7.73-7.86 (3H, m), 8.20 (2H, br s), 8.55(2H, d, J=6Hz) Mass: M⁺² 243, M⁺¹ 242, M⁺ 241, m/e 209, 195

EXAMPLE 53

A mixture of 2-amino-5-(4-aminophenylthio)thiazole, (4.0 g) in a mixtureof acetic acid (40 ml) and acetic anhydride (2.2 g) was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated underreduced pressure and the residue was triturated with aqueous sodiumbicarbonate. The precipitates were collected by filtration, washed withwater and dried in vacuo to give solid. The solid was subjected tocolumn chromatography on silica gel (silica gel 60, 70-230 mesh; Merck:150 g) and eluted with a mixture of chloroform and methanol (10:1). Thefractions containing the objective compound were combined andconcentrated under reduced pressure to give2-amino-5-(4-acetylaminophenylthio)thiazole (2.1 g, yield: 44.2%). mp:240°-245° C. (dec.)

IR (Nujol): 3400, 3325, 3200, 1660, 1605, 1595, 1320 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 2.10 (3H, s), 7.26 (2H, d, J=8Hz), 7.30 (1H,s), 7.50 (2H, s), 7.67 (2H, d, J=8Hz), 10.03 (1H, s) Mass: M⁺¹ 266, M265, m/e 223, 207, 190

EXAMPLE 54

To a mixture of 2-amino-5-(4-methanesulfonylaminophenylthio)thiazole(2.0 g) in chloroform (100 ml) was added dropwise the solution of3-chloroperbenzoic acid (1.6 g) in chloroform (50 ml) at 5° C. under icecooling with stirring. The mixture was stirred at 5° C. for 2.5 hours.The reaction mixture was washed with aqueous sodium bicarbonate and theprecipitates were collected by filtration. The solid was washed withaqueous sodium bicarbonate and water, dried in vacuo to give2-amino-5-(4-methanesulfonylaminophenylsulfinyl)thiazole (1.95 g, yield:92.6%). mp: 201°-203° C. (.dec.)

IR (Nujol): 3320, 3250, 3100, 1615, 1515, 1325, 1220, 1150 cm⁻¹

NMR (DMSO-d₆, 60 MHZ, ppm): 3.17 (3H, s), 7.43 (2H, d, J=8Hz), 7.67 (2H,d, J=8Hz), 7.73 (1H, s), 7.83 (2H, s), 10.23 (1H, s) Mass: m/e 301, 222,190, 146, 124, 100

EXAMPLE 55

A mixture of 2-acetylamino-5-chlorothiazole (1.76 g),4-hydroxythiophenol (1.3 g) and potassium carbonate (2 g) inN,N-dimethylformamide (30 ml) was heated at 120° C. for 2.5 hours withstirring. The reaction mixture was poured into ice water. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g,yield: 56.6%). mp: 265°-267° C.

IR (Nujol): 3300, 3200, 1675, 1600, 1570, 1305, 1260 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.14 (3H, s), 6.75 (2H, d, J=9Hz), 7.20(2H, d, J=9Hz), 7.63 (1H, s), 9.69 (1H, s), 12.28 (1H, s) Mass: M⁺¹ 267,M 266, m/e 224, 191, 182, 165, 137

EXAMPLE 56

A mixture of 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g) in amixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) wasrefluxed for 4.5 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 10 using aqueous sodium hydroxideunder ice cooling. The precipitates were collected by filtration andrecrystallized from a mixture of ethanol and water (3:1) to give2-amino-5-(4-hydroxyphenylthio)thiazole (1.05 g, yield: 84.0%). mp:187°-188° C.

IR (Nujol): 3450, 3350, 3200, 1625, 1600, 1500, 1320, 1245 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 6.74 (2H, d, J=9Hz), 7.08 (2H, d, J=9Hz),7.13 (1H, s), 7.34 (2H, s), 9.58 (1H, s) Mass: M⁺¹ 225, M 224, m/e 192,182, 165, 137

EXAMPLE 57

A mixture of 2-acetylamino-5-chlorothiazole (1.76 g),4-methoxythiophenol (1.5 g) and potassium carbonate (2.0 g) inN,N-dimethylformamide (30 ml) was heated at 120° C. for 3.5 hours withstirring. The reaction mixture was poured into ice water and theprecipitates were collected by filtration to give solid. The solid wasrecrystallized from ethanol to give2-acetylamino-5-(4-methoxyphenylthio)thiazole (2.2 g, Yield: 78.6%). mp:190°-191° C. IR (Nujol): 3175, 1695, 1565, 1490, 1295, 1250 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.14 (3H, s), 3.74 (3H, s), 6.93 (2H, d,J=9Hz), 7.25 (2H, d, J=9Hz), 7.68 (1H, s), 12.31 (1H, s) Mass: M⁺¹ 281,M 280, m/e 238, 205, 196, 151

EXAMPLE 58

A mixture of 2-acetylamino-5-(4-methoxyphenylthio)thiazole (1.7 g) in amixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) wasrefluxed for 4 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 10 using aqueous sodium hydroxideunder cooling. The precipitates were collected by filtration, washedwith water and recrystallized from ethanol to give2-amino-5-(4-methoxyphenylthio)thiazole (1.25 g, yield: 86.8%). mp:119°-120° C.

IR (Nujol): 3400, 3275, 3100, 1635, 1595, 1520, 1460, 1240 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 3.73 (3H, s), 6.91 (2H, d, J=9Hz), 7.17(1H, s), 7.21 (2H, d, J=9Hz), 7.39 (2H, s) Mass: M⁺¹ 239, M 238, m/e206, 196, 151

EXAMPLE 59

A mixture of 2-acetylamino-5-chlorothiazole (1.76 g),5-mercapto-2-methyl-1,3,4-thiadiazole (1.3 g) and potassium carbonate(2.0 g) in N,N-dimethylformamide (40 ml) was heated at 120° C. for 4hours with stirring. The reaction mixture was concentrated under reducedpressure and water was added to this residue. The mixture was extractedwith a mixture of tetrahydrofuran and ethyl acetate (1:1), washed withaqueous saturated sodium chloride and dried over magnesium sulfate. Thesolvent was concentrated under reduced pressure to give solid. The solidwas subjected to column chromatography on silica gel (silica gel 60,70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform andmethanol (10:1). The fractions containing the objective compound werecombined and concentrated under reduced pressure to give2-acetylamino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (1.65 g,yield: 60.7%). mp: 242°-244° C. IR (Nujol): 3250, 1695, 1550, 1300 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.19 (3H, s), 2.63 (3H, s), 7.95 (1H, s),12.58 (1H, s) Mass: M⁺¹ 273, M 272, m/e 230, 188, 155, 131

EXAMPLE 60

A mixture of2-acetylamino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (3.3 g) ina mixture of ethanol (70 ml), tetrahydrofuran (50 ml) and aqueous6N-hydrochloric acid (200 ml) was refluxed for 6.5 hours with stirring.The reaction mixture was concentrated under reduced pressure and theresidue was dissolved in water. The solution was adjusted to pH 8.5using aqueous sodium bicarbonate and extracted with a mixture oftetrahydrofuran and ethyl acetate (1:1). The organic layer was washedwith aqueous saturated sodium chloride and dried over magnesium sulfate.The organic solvent was concentrated under reduced pressure to givesolid. The solid was subjected to column chromatography on silica gel(silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture ofchloroform and methanol (10:1). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to give2-amino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (0.85 g, Yield:58.2%). mp: 203°-205° C. (dec.)

IR (Nujol): 3450, 3300, 3100, 1640, 1520, 1485, 1220 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.63 (3H, s), 7.42 (1H, s), 7.75 (2H, s)Mass: M⁺¹ 231, M 230, m/e 188, 154, 131, 113

EXAMPLE 61

A mixture of 2-acetylamino-5-chlorothiazole (1.76 g),5-mercapto-1-methyl-1H-tetrazole (1.2 g) and potassium carbonate (2 g)in N,N-dimethylformamide (40 ml) was heated at 130° C. for 3 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitates werecollected by filtration, washed with water and dried in vacuo to givesolid. The solid was subjected to column chromatography on silica gel(silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture ofchloroform and methanol (10:1). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to give2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (2.1 g, yield:82.0%). mp: 208°-210° C.

IR (Nujol): 3450, 3250, 3150, 1690, 1665, 1550, 1295, 1225 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.17 (3H, s), 4.11 (3H, s), 7.89 (1H, s),12.51 (1H, s) Mass: M⁺¹ 257, M 256, m/e 214, 173, 159, 131

EXAMPLE 62

A mixture of 2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole(2.0 g) in a mixture of ethanol (20 ml) and aqueous 6N-hydrochloric acid(5 ml) was refluxed for 4 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was adjusted to pH 8using aqueous sodium bicarbonate under ice cooling. The precipitateswere collected by filtration, washed with water and the solid wasrecrystallized from ethanol to give2-amino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (0.81 g, yield:48.5%). mp: 186°-188° C. (dec.)

IR (Nujol): 3400, 3250, 3150, 1612, 1510, 1490, 1215 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 4.03 (3H, s), 7.38 (1H, s), 7.63 (2H, s)Mass: M⁺¹ 215, M 214, m/e 131, 89, 83

EXAMPLE 63

A mixture of 2-amino-5-bromothiazole hydrochloride (2.2 g),4-amino-2-mercaptopyrimidine (2.2 g) and potassium carbonate (6.5 g) inN,N-dimethylformamide (100 ml) was heated at 90° C. for 2.5 hours withstirring. The reaction mixture was concentrated under reduced pressureand water was added to this residue. The solution was extracted with amixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueoussaturated sodium chloride and dried over magnesium sulfate. The solventwas concentrated under reduced pressure to give solid. The solid wassubjected to column chromatography on silica gel (silica gel 60, 70-230mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol(10:1). The fractions containing the objective compound were combinedand concentrated under reduced pressure to give solid. The solid wastriturated with ethanol to give2-amino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.25 g, yield: 55.6%).mp: 185°-187° C. (dec.)

IR (Nujol): 3450, 3300, 3175, 3100, 1645, 1630, 1580, 1545, 1340 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 6.16 (1H, d, J=6Hz), 6.99 (2H, s), 7.07(1H, s), 7.32 (2H, s), 7.86 (1H, d, J=6Hz) Mass: M⁺¹ 226, M 225, m/e183, 139

EXAMPLE 64

A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (1.15 g),2-mercaptopyrimidine (0.6 g) and potassium carbonate (1.7 g) inN,N-dimethylformamide (20 ml) was heated at 90° C. for 3.5 hours withstirring. The reaction mixture was poured into ice water. The mixturewas extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1),washed with aqueous saturated sodium chloride and dried over magnesiumsulfate. The solvent was concentrated under reduced pressure to givesolid. The solid was subjected to column chromatography on silica gel(silica gel 60, 70-230 mesh,; Merck: 100 g) and eluted with a mixture ofchloroform and methanol (10:1). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to give2-amino-4-methyl-5-(2-pyrimidinylthio)thiazole (0.65 g, yield: 58.0%).mp: 165°-170° C. (dec.) IR (Nujol): 3300, 3175, 1630, 1555, 1490, 1320cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.10 (3H, s), 7.24-7.33 (1H, m), 7.33 (2H,s), 8.64 (2H, d, J=5Hz) Mass: M⁺¹ 225, M 224, m/e 209, 191, 182, 166,145

EXAMPLE 65

A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (4.5 g),2-mercaptopyridine (2.3 g) and potassium carbonate (7.0 g) inN,N-dimethylformamide (100 ml) was heated at 90° C. for 3 hours withstirring. The reaction mixture was concentrated under reduced pressureand water was added to this residue. The mixture was extracted with amixture of tetrahydrofuran and ethyl acetate, washed with aqueoussaturated sodium chloride and dried over magnesium sulfate. The solventwas concentrated under reduced pressure to give solid. The solid wassubjected to column chromatography on silica gel (silica gel 60, 70-230mesh; Merck: 300 g) and eluted with a mixture of chloroform and methanol(10:1). The fractions containing the objective compound were combinedand concentrated under reduced pressure to give oil. Again the oil wassubjected to column chromatography on silica gel (silica gel 60, 70-230mesh; Merck: 200 g) and eluted with a mixture of dichloromethane andacetone (5:1). The fractions containing the objective compound werecombined and concentrated under reduced pressure to give2-amino-4-methyl-5-(2-pyridylthio)thiazole (2.1 g, yield: 47.9%).

NMR (DMSO-d₆, 200 MHZ, ppm): 2.13 (3H, s), 6.97 (1H, m), 7.15 (1H, m),7.28 (2H, s), 7.65 (1H, m), 8.40 (1H, m) Mass: M⁺¹ 224, M 223, m/e 208,190, 181, 145, 111

EXAMPLE 66

A mixture of 2-amino-4-methyl-5-(2-pyridylthio)thiazole (1.7 g) and3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (20 ml) anddichloromethane (50 ml) was stirred at 5° C. for 3.5 hours. The reactionmixture was washed with aqueous sodium bicarbonate and dried overmagnesium sulfate. The solvent was concentrated under reduced pressureto give solid. The solid was subjected to column chromatography onsilica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with amixture of chloroform and methanol (10:1). The fractions containing theobjective compound were combined and concentrated under reduced pressureto give 2-amino-4-methyl-5-(2-pyridylsulfinyl)thiazole (0.95 g, yield:52.2 %). mp: 190°-193° C. (dec.)

NMR (DMSO-d₆, 200 MHZ, ppm): 2.38 (3H, s), 7.50-7.58 (1H, m), 7.70 (2H,s), 7.96 (1H, d, J=8Hz), 8.07-8.16 (1H, m), 8.6-8.63 (1H, m) Mass: M⁺¹240, M 239, m/e 223, 191, 161, 129, 111

EXAMPLE 67

A mixture of 2-acetylamino-5-bromothiazole (1.9 g), 2-mercaptoimidazole(0.9 g) and potassium carbonate (1.5 g) in N,N-dimethylformamide (30 ml)was heated at 90° C. for 2.5 hours with stirring. The reaction mixturewas concentrated under reduced pressure and the residue was extractedwith methanol. The solvent was concentrated under reduced pressure togive solid. The solid was subjected to column chromatography on silicagel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixtureof chloroform and methanol (10:1). The fraction containing the objectivecompound were combined and concentrated under reduced pressure to give2-acetylamino-5-(2-imidazolylthio)thiazole (1.8 g, yield: 87.4%). mp:230°-235° C. (dec.) IR (Nujol): 3150, 3100, 1710, 1550, 1290 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.1 (3H, s), 6.80 (1H, s), 7.08 (2H, s),7.6 (1H, s), 12.3 (1H, s) Mass: M⁺¹ 241, M 240, m/e 198, 156, 100

EXAMPLE 68

A mixture of 2-acetylamino-5-(2-imidazolylthio)thiazole (1.8 g) in amixture of concentrated hydrochloric acid (10 ml) and ethanol (50 ml)was refluxed for 5 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The solution was adjusted to pH 8.5 using sodium bicarbonate withcooling. The precipitates were collected by filtration, washed withwater and dried in vacuo to give 2-amino-5-(2-imidazolylthio)thiazole(0.35 g). The filtrate was extracted with a mixture of tetrahydrofuranand ethyl acetate (1:1), washed with aqueous saturated sodium chlorideand dried over magnesium sulfate. The solvent was concentrated underreduced pressure to give solid. The solid was subjected to columnchromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g)and eluted with a mixture of chloroform and methanol (10:1). Thefractions containing the objective compound were combined andconcentrated under reduced pressure to give2-amino-5-(2-imidazolylthio)thiazole (0.55 g). Total amount of2-amino-5-(2-imidazolylthio)thiazole was 0.90 g (yield: 60.4%). mp:209°-211° C. (dec.) IR (Nujol): 3450, 3300, 1630, 1520, 1315 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.05 (2H, s), 7.15 (1H, s), 7.36 (2H, s)Mass: M⁺¹ 199, M 198, m/e 156, 139, 100

EXAMPLE 69

A mixture of 2-acetylamino-5-bromothiazole (1.8 g),3-hydroxy-2-mercaptopyridine (1.3 g) and potassium carbonate (2.0 g) inN,N-dimethylformamide (40 ml) was heated at 90° C. for 3.5 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The mixture was extractedwith a mixture of tetrahydrofuran and ethyl acetate (1:1), washed withaqueous saturated sodium chloride and dried over magnesium sulfate. Thesolvent was concentrated under reduced pressure to give solid. The solidwas subjected to column chromatography on silica gel (silica gel 60,70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform andmethanol (10:1). The fractions containing the objective compound werecombined and concentrated under reduced pressure to give2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2.4 g, yield:89.9%). mp: 236°-238° C. (dec.) IR (Nujol): 3175, 1690, 1565, 1300 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.16 (3H, s), 7.02-7.17 (3H, m), 7.58 (1H,s), 7.83 (1H, d, J=6Hz), 10.70 (1H, s), 12.30 (1H, s) Mass: M⁺¹ 268, M267, m/e 225, 183, 127

EXAMPLE 70

A mixture of 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2 g)in a mixture of ethanol (40 ml), tetrahydrofuran (20 ml) and aqueous6N-hydrochloric acid (13 ml) was refluxed for 5 hours with stirring. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in water. The solution was adjusted to pH 8.5 usingaqueous sodium bicarbonate and extracted with a mixture oftetrahydrofuran and ethyl acetate (1:1). The organic layer was washedwith aqueous saturated sodium chloride and dried over magnesium sulfate.The solvent was concentrated under reduced pressure to give2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (1.15 g, yield: 68.9%).mp: 128°-130° C.

IR (Nujol): 3500, 3400, 3300, 1640, 1570, 1520, 1500, 1330, 1200 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 6.97-7.11 (3H, m), 7.29 (2H, s), 7.82 (1H,d, J=6Hz), 10.57 (1H, s) Mass: M⁺¹ 226, M 225, m/e 183, 139, 100

EXAMPLE 71

To a mixture of 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (4.6 g) ina mixture of chloroform (100 ml), dichloromethane (200 ml) andN,N-dimethylformamide (50 ml) was added dropwise the solution of3-chloroperbenzoic acid (4.3 g) in chloroform (50 ml) at 5° C. withstirring. The mixture was stirred at room temperature for 5 hours. Thereaction mixture was extracted with aqueous diluted hydrochloric acidand the aqueous layer was washed with ethyl acetate. The aqueous layerwas adjusted to pH 5.7 using sodium bicarbonate and extracted with amixture of tetrahydrofuran and ethyl acetate (1:1). The organic layerwas washed with aqueous saturated sodium chloride and dried overmagnesium sulfate. The solvent was concentrated under reduced pressureto give solid. The solid was subjected to column chromatography onsilica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with amixture of chloroform and methanol (10:1). The fractions containing theobjective compound were combined and concentrated under reduced pressureto give 2-amino-5-(3-hydroxypyridin-2-ylsulfinyl)thiazole (0.65 g,yield: 12.2%). mp: 155-158° C. (dec.) IR (Nujol): 3300, 3150, 1620,1565, 1515, 1300 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.29-7.40 (2H, m), 7.59 (1H, s), 7.75 (2H,s), 8.15 (1H, br s) Mass: m/e 225, 220, 205

EXAMPLE 72

A mixture of 2-acetylamino-5-bromothiazole (1 g), 3-mercaptopyridinehydrochloride (1 g) and potassium carbonate (1.5 g) inN,N-dimethylformamide (10 ml) was heated at 90° C. for 4.5 hours withstirring. The reaction mixture was poured into ice water. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give 2-acetylamino-5-(3-pyridylthio)thiazole (0.9 g, yield:81.8%). mp: 203°-205° C. (dec.) IR (Nujol): 3170, 1700, 1570, 1300 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.16 (3H, s), 7.33-7.39 (1H, s), 7.60 (1H,d, J=8Hz), 7.81 (1H, s), 8.42-8.54 (2H, m), 12.45 (1H, s) Mass: M⁺¹ 252,M 251, m/e 209, 176, 167, 111

EXAMPLE 73

A mixture of 2-acetylamino-5-(3-pyridylthio)thiazole (8.5 g) in amixture of ethanol (160 ml), tetrahydrofuran (50 ml) and aqueous 6Nhydrochloric acid (100 ml) was refluxed for 4 hours with stirring. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in water. The solution was adjusted to pH 8.5 usingaqueous sodium bicarbonate and the precipitates were collected byfiltration, washed with water and dried in vacuo to give2-amino-5-(3-pyridylthio)thiazole (5.6 g yield: 78.9%). mp: 140°-142° C.IR (Nujol): 3400, 3300, 3125, 1630, 1530, 1490 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.30 (1H, s), 7.32-7.39 (1H, m), 7.55 (2H,s), 7.57-7.61 (1H, m), 8.40 (2H, d, J=7Hz) Mass: M⁺¹ 210, M 209, m/e167, 122, 99

EXAMPLE 74

To a mixture of 2-amino-5-(3-pyridylthio)thiazole (3.0 g) in a mixtureof dichloromethane (100 ml) and chloroform (100 ml) was added dropwisethe solution of 3-chloroperbenzoic acid (3.4 g) in dichloromethane (50ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 3hours. The reaction mixture was washed with aqueous sodium bicarbonateand the aqueous layer was extracted with a mixture of tetrahydrofuranand ethyl acetate (1:1), washed with aqueous saturated sodium chlorideand dried over magnesium sulfate. The solvent was concentrated underreduced pressure and the residue was recrystallized from ethanol to give2-amino-5-(3-pyridylsulfinyl)thiazole (1.2 g, yield: 37.2%). mp:178°-179° C.

IR (Nujol): 3300, 3150, 1630, 1580, 1520, 1485, 1325, 1220 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.58-7.70 (1H, m), 7.80 (1H, s), 8.00 (2H,s), 7.98-8.05 (1H, m), 8.72 (2H, br s) Mass: M⁺¹ 226, M 225, m/e 209,177, 147

EXAMPLE 75

A mixture of 2-amino-5-(3-pyridylsulfinyl)thiazole (1.6 g) and3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (150 ml),dichloromethane (50 ml) and N,N-dimethylformamide (5 ml) was stirred atroom temperature for 3 hours. The reaction mixture was extracted withdiluted hydrochloric acid and washed with ethyl acetate. The aqueouslayer was adjusted to pH 8.5 using sodium bicarbonate and the mixturewas extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1).The organic layer was washed with water and dried over magnesiumsulfate. The solvent was concentrated under reduced pressure and theresidue was triturated with ethanol to give2-amino-5-(3-pyridylsulfonyl)thiazole (0.30 g, yield: 17.5%). mp:218°-220° C. (dec.) IR (Nujol): 3420, 3300, 1650, 1520, 1310 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.63-7.70 (1H, m), 7.78 (1H, s), 8.20 (2H,s), 8.27 (1H, d, J=8Hz), 8.85 (1H, d, J=4Hz), 9.06 (1H, s)

Mass: M⁺¹ 242, M 241, m/e 177, 135, 99

EXAMPLE 76

A mixture of 2-acetylamino-5-bromothiazole (2.2 g),2-mercapto-5-trifluoromethylpyridine (1.9 g) and potassium carbonate(2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 4.5hours with stirring. The reaction mixture was concentrated under reducedpressure and the residue was triturated with water. The precipitateswere collected by filtration, washed with water and dried in vacuo togive 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g,yield: 100%). mp: 165°-170° C. (dec.) IR (Nujol): 3175, 1695, 1640,1600, 1565, 1330 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.19 (3H, s), 7.21 (1H, d, J=12Hz), 7.83(1H, s), 8.04-8.15 (1H, m), 8.18 (1H, br s), 12.53 (1H, s) Mass: M⁺¹321, M 320, M 319, m/e 277, 235, 191

EXAMPLE 77

A mixture of 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole(3.2 g) in a mixture of ethanol (60 ml), tetrahydrofuran (30 ml) andaqueous 6N-hydrochloric acid (10 ml) was refluxed for 3 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was dissolved in water. The solution was adjusted to pH8.5 using aqueous sodium bicarbonate and extracted with mixture oftetrahydrofuran and ethyl acetate (1:1) and dried over magnesiumsulfate. The solvent was concentrated under reduced pressure to givesolid. The solid was subjected to column chromatography on silica gel(silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture ofchloroform and methanol (10:1). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to give2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (2.1 g, yield:75.8%). mp: 135°-138° C.

IR (Nujol): 3400, 3300, 3100, 1640, 1600, 1560, 1520, 1330 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.26 (1H, d, J=8Hz), 7.33 (1H, s), 7.66(2H, s), 7.81 (1H, d, J=8Hz), 8.80 (1H, s) Mass: M⁺¹ 278, M 277, m/e235, 191, 146, 131

EXAMPLE 78

To a solution of 2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole(0.6 g) in dichloromethane (20 ml) was added portionwise3-chloroperbenzoic acid (0.6 g) at 5° C. with stirring. The mixture wasstirred at 5° C. for 3 hours. The reaction mixture was washed withaqueous sodium bicarbonate and dried over magnesium sulfate. The solventwas concentrated under reduced pressure to give solid. The solid wassubjected to column chromatography on silica gel (silica gel 60, 70-230mesh; Merck: 30 g) and eluted with a mixture of chloroform and methanol(10:1). The fractions containing the objective compound were combinedand concentrated under reduced pressure to give2-amino-5-(5-trifluoromethylpyridin-2-ylsulfinyl)thiazole (0.52 g,yield: 81.9%). mp: 144°-145° C.

NMR (DMSO-d₆, 200 MHZ, ppm): 7.82 (1H, s), 7.92 (2H, s), 8.21 (1H, d,J=8Hz), 8.56 (1H, d, J=8Hz), 9.08 (1H, s) Mass: M 293, m/e 277, 245,226, 179, 147

EXAMPLE 79

A mixture of 2-acetylamino-5-bromothiazole (2.2 g),4-amino-2-mercaptopyrimidine (1.3 g) and potassium carbonate (2.0 g) inN,N-dimethylformamide (50 ml) was heated at 90° C. for 2 hours withstirring. The reaction mixture was concentrated under reduced pressureand the residue was triturated with water. The precipitation wascollected by filtration, washed with water and dried in vacuo to givesolid. The solid was subjected to column chromatography on silica gel(silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture ofchloroform and methanol (10:1). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to give2-acetylamino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.3 g, yield:48.7%). mp: 255°-258° C. (dec.)

IR (Nujol): 3400, 3350, 3200, 1692, 1650, 1585, 1325, 1300 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.16 (3H, s), 6.17 (1H, d, J=6Hz), 7.02(2H, s), 7.59 (1H, s), 7.85 (1H, d, J=6Hz), 12.31 (1H, s) Mass: M⁺¹ 268,M 267, m/e 225, 205, 183

EXAMPLE 80

Starting from 2-acetylamino-5-bromothiazole,2-acetylamino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (0.35 g, yield:28.8%) was obtained according to a similar manner to that of Example 67.

IR (Nujol): 3150, 1665, 1565, 1535, 1300, 1275, 1230 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.18 (3H, s), 6.25 (1H, d, J=6Hz), 7.70(1H, s), 7.93 (1H, d, J=6Hz), 12.0-12.6 (2H, m) Mass: M⁺¹ 269, M 268,m/e 259, 197, 135

EXAMPLE 81

A mixture of 2-acetylamino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (3.7g) in a mixture of ethanol (100 ml), tetrahydrofuran (40 ml) and aqueous6N-hydrochloric acid (20 ml) was refluxed for 6.5 hours with stirring.The reaction mixture was concentrated under reduced pressure and theresidue was dissolved in water. The solution was adjusted to pH 8.5using aqueous sodium bicarbonate. The precipitates were collected byfiltration, washed with water and dried in vacuo to give solid. Thesolid was subjected to column chromatography on silica gel (silica gel60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroformand methanol (10:1). The fractions containing the objective compoundwere combined and concentrated under reduced pressure to give2-amino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (0.45 g, yield: 14.5%).mp: 210°-220° C. (dec.) IR (Nujol): 3450, 3350, 3125, 1675, 1510,1230cm⁻¹

NMR (DMSO-d6 200 MHZ, ppm): 5.45 (1H, d, J=7Hz), 7.30-7.40 (3H, m), 7.64(1H, m) Mass: m/e 220, 205, 132, 112

EXAMPLE 82

Starting from 2-acetylamino-5-bromothiazole,2-acetylamino-5-(4-methylpyrimidin-2-ylthio)thiazole (2.89 g, yield:48.0%) was obtained according to a similar manner to that of Example 67.mp: 210° C. (dec.) IR (Nujol): 3170, 1720, 1695, 1575, 1555, 1335 cm⁻¹NMR (DMSO-d₆, 200 MHZ, ppm): 2.19 (3H, s), 2.39 (3H, s), 7.16 (1H, d,J=5Hz), 7.70 (1H, s), 8.46 (1H, d, J=5Hz), 12.38 (1H, s) Mass: M⁺² 268,M⁺¹ 267, M 266, m/e 224, 182, 165

EXAMPLE 83

Starting from 2-acetylamino-5-(4-methylpyrimidin-2-ylthio)thiazole,2-amino-5-(4-methylpyrimidin-2-ylthio)thiazole (0.40 g, yield: 16.4%)was obtained according to a similar manner to that of Example 58. mp:158°-159° C.

IR (Nujol): 3430, 3280, 3100, 1620, 1565, 1520, 1490, 1330, 1210 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.39 (3H, s), 7.14 (1H, d, J=5Hz), 7.15(1H, s), 7.43 (2H, s), 8.47 (1H, d, J=5Hz) Mass: M⁺² 226, M⁺¹ 225, M224, m/e 182, 138

Analysis Calcd. for C₈ H₈ N₄ S₂ : C 42.84, H 3.59, N 24.99; Found: C42.81, H 3.50, N 24.86.

EXAMPLE 84

To a solution of 2-amino-5-(2-pyrimidinylthio)thiazole (1.0 g) in apyridine (20 ml) was dropwise added methanesulfonyl chloride (0.8 ml) at5° C. with stirring. The mixture was stirred at room temperature for 24hours. The reaction mixture was concentrated under reduced pressure andwater was added to this residue. The mixture was extracted with amixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueoussaturated sodium chloride and dried over magnesium sulfate. The solutionwas concentrated under reduced pressure to give solid. The solid wasrecrystallized from 50% ethanol to give2-methanesulfonylamino-5-(2-pyrimidinylthio)thiazole (0.60 g, yield:43.8%). mp: 200° C. (dec.) IR (Nujol): 3120, 1585, 1545, 1440, 1305,1140 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 2.98 (3H, s), 7.35 (1H, t, d=7Hz), 7.76(1H, s), 8.71 (2H, d, J=7Hz), 12.89 (1H, br s) Mass: M⁺² 290, M⁺¹ 289, M288, m/e 209, 168

Analysis Calcd. for C₈ H₈ N₄ O₂ S₃ : C 33.32, H 2.80, N 19.43; Found: C33.04, H 2.74, N 19.06.

EXAMPLE 85

Starting from 2-amino-5-(2-pyrimidinylthio)thiazole,2-amino-5-(2-pyrimidinylsulfinyl)thiazole (0.52 g, yield: 32.2%) wasobtained according to a similar manner to that of Example 66. mp: 206°C. (dec.)

IR (Nujol): 3300, 3200, 1615, 1565, 1545, 1520, 1230, 1150 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.67 (1H, t, J=5Hz), 7.73 (1H, s), 7.87(2H, s), 8.99 (2H, d, J=5Hz) Mass: M 226, m/e 210, 178, 168, 147

Analysis Calcd. for C₇ H₆ N₄ OS₂ : C 37.16, H 2.67, N 24.76; Found: C36.78, H 2.62, N 24.62.

EXAMPLE 86

Starting from 2-amino-5-(2-pyrimidinylthio)thiazole,2-amino-5-(2-pyrimidinylsulfonyl)thiazole (0.464 g, yield: 8.1%) wasobtained according to a similar manner to that of Example 75. mp: 214°C. (dec.)

IR (Nujol): 3400, 3100, 1615, 1570, 1515, 1335, 1210, 1140 cm⁻¹

NMR (DMSO-d₆, 200 MHZ, ppm): 7.73 (1H, s), 7.80 (1H, t, d=5Hz), 8.23(2H, s), 9.05 (2H, d, J=5Hz) Mass: M⁺² 244, M⁺¹ 243, M 242, m/e 178, 136

What we claim is:
 1. A compound of the formula: ##STR6## wherein R¹ ishydrogen or acyl which may be substituted with halogen,R² is hydrogen,lower alkyl, hydroxy(lower)alkyl, halogen or carboxy, A is ##STR7##wherein m is 0, 1 or 2, and R³ is pyridyl, which may be substituted withlower alkyl, amino, hydroxy, or halo(lower)alkyl,and pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1, wherein R¹ ishydrogen, lower alkanoyl or benzoyl which may be substituted withhalogen.
 3. A compound of claim 2, wherein R¹ is hydrogen.
 4. A compoundof claim 3, wherein R² is hydrogen.
 5. The compound of claim 1, whereinm is 0 or
 1. 6. The compound of claim 5, wherein m is
 1. 7. The compoundof claim 5, wherein R¹ is hydrogen, lower alkanoyl, lower alkanesulfonylor benzoyl which may be substituted with halogen.
 8. The compound ofclaim 7, wherein R³ is pyridyl, which may be substituted with loweralkyl, amino, hydroxy or halo(lower)alkyl.
 9. The compound of claim 8,wherein m is
 0. 10. The compound of claim 8, wherein m is
 1. 11. Acompound of the formula: ##STR8## wherein R¹ is lower alkanesulfonylwhich may be substituted with halogen,R² is hydrogen, lower alkyl,hydroxy(lower)alkyl, halogen or carboxy, A is ##STR9## wherein m is 0, 1or 2, and R³ is pyridyl, which may be substituted with lower alkyl,amino, hydroxy, or halo(lower)alkyl,and pharmaceutically acceptablesalts thereof.